Lipid Metabolism

Introduction

• Dietary lipids Lipids Lipids are a diverse group of hydrophobic organic molecules, which include fats, oils, sterols, and waxes. Fatty Acids and Lipids: 
  • Dense storage forms of energy
  • Provide essential fatty acids Essential fatty acids Long chain organic acid molecules that must be obtained from the diet. Examples are linoleic acids and linolenic acids. Fatty Acids and Lipids
  • Essential in absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption of fat-soluble vitamins
  • Made mostly of triacylglycerols Triacylglycerols Fatty Acids and Lipids and cholesterol Cholesterol The principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils. Cholesterol Metabolism
  • Can be found in 2 forms at room temperature: 
    • Fats Fats The glyceryl esters of a fatty acid, or of a mixture of fatty acids. They are generally odorless, colorless, and tasteless if pure, but they may be flavored according to origin. Fats are insoluble in water, soluble in most organic solvents. They occur in animal and vegetable tissue and are generally obtained by boiling or by extraction under pressure. They are important in the diet (dietary fats) as a source of energy. Energy Homeostasis: solid, more saturated fatty acids Saturated fatty acids Fatty Acids and Lipids (FAs) 
    • Oils: liquid, more unsaturated FAs
• Lipid sources:
  • Dietary lipids Lipids Lipids are a diverse group of hydrophobic organic molecules, which include fats, oils, sterols, and waxes. Fatty Acids and Lipids
  • Synthesis Synthesis Polymerase Chain Reaction (PCR) in liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy
• Lipid metabolism is tightly regulated:
  • Disorders in metabolism result in dyslipidemia
  • Wide-ranging health repercussions

Review of lipid structure

• TAGs:
  • Glycerol backbone: a 3-carbon chain with each carbon attached to an alcohol group 
  • Fatty acids Acids Chemical compounds which yield hydrogen ions or protons when dissolved in water, whose hydrogen can be replaced by metals or basic radicals, or which react with bases to form salts and water (neutralization). An extension of the term includes substances dissolved in media other than water. Acid-Base Balance: a hydrocarbon chain with a carboxyl group at one end
  • Each carbon on the glycerol backbone is bound to the carboxy end of a fatty acid chain by an ester bond.
• Phospholipids: 
  • Glycerol backbone + 2 FA FA Inhaled Anesthetics + phosphate group Phosphate group Nucleic Acids
  • Additional molecules are also bound to the phosphate group Phosphate group Nucleic Acids (e.g., choline).
• Cholesterol Cholesterol The principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils. Cholesterol Metabolism: 
  • Sterols Sterols Steroids with a hydroxyl group at c-3 and most of the skeleton of cholestane. Additional carbon atoms may be present in the side chain. Fatty Acids and Lipids: consist of 4 adjacent hydrocarbon rings
  • Cholesterol Cholesterol The principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils. Cholesterol Metabolism esters (storage form of cholesterol Cholesterol The principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils. Cholesterol Metabolism): cholesterol Cholesterol The principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils. Cholesterol Metabolism + 1 FA FA Inhaled Anesthetics

Digestion of Lipids

Lipids Lipids Lipids are a diverse group of hydrophobic organic molecules, which include fats, oils, sterols, and waxes. Fatty Acids and Lipids are broken down and packaged into micelles Micelles Particles consisting of aggregates of molecules held loosely together by secondary bonds. The surface of micelles are usually comprised of amphiphatic compounds that are oriented in a way that minimizes the energy of interaction between the micelle and its environment. Liquids that contain large numbers of suspended micelles are referred to as emulsions. Malabsorption and Maldigestion (spherical aggregates, inside lipophilic and outside hydrophilic Hydrophilic Aminoglycosides), and are readily absorbed by the membranes of enterocytes.

Enzymatic digestion Digestion Digestion refers to the process of the mechanical and chemical breakdown of food into smaller particles, which can then be absorbed and utilized by the body. Digestion and Absorption

• Lipases are key enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body’s constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes that break down triglycerides Triglycerides Fatty Acids and Lipids (via hydrolysis Hydrolysis The process of cleaving a chemical compound by the addition of a molecule of water. Proteins and Peptides):
  • Lingual lipase Lingual lipase Digestion and Absorption (from salivary glands Salivary glands The salivary glands are exocrine glands positioned in and around the oral cavity. These glands are responsible for secreting saliva into the mouth, which aids in digestion. There are 3 major paired salivary glands: the sublingual, submandibular, and parotid glands. Salivary Glands: Anatomy, activated by acid in the stomach Stomach The stomach is a muscular sac in the upper left portion of the abdomen that plays a critical role in digestion. The stomach develops from the foregut and connects the esophagus with the duodenum. Structurally, the stomach is C-shaped and forms a greater and lesser curvature and is divided grossly into regions: the cardia, fundus, body, and pylorus. Stomach: Anatomy)
  • Gastric lipase Gastric lipase Digestion and Absorption (from chief cells Chief cells Epithelial cells that line the basal half of the gastric glands. Chief cells synthesize and export an inactive enzyme pepsinogen which is converted into the highly proteolytic enzyme pepsin in the acid environment of the stomach. Stomach: Anatomy)
  • Pancreatic lipase Lipase An enzyme of the hydrolase class that catalyzes the reaction of triacylglycerol and water to yield diacylglycerol and a fatty acid anion. It is produced by glands on the tongue and by the pancreas and initiates the digestion of dietary fats. Malabsorption and Maldigestion (from the exocrine pancreas Exocrine pancreas The major component (about 80%) of the pancreas composed of acinar functional units of tubular and spherical cells. The acinar cells synthesize and secrete several digestive enzymes such as trypsinogen; lipase; amylase; and ribonuclease. Secretion from the exocrine pancreas drains into the pancreatic ductal system and empties into the duodenum. Pancreas: Anatomy; the most important)
• This breakdown begins in the mouth with lingual lipase Lingual lipase Digestion and Absorption, but the majority of the process occurs in the small intestine Small intestine The small intestine is the longest part of the GI tract, extending from the pyloric orifice of the stomach to the ileocecal junction. The small intestine is the major organ responsible for chemical digestion and absorption of nutrients. It is divided into 3 segments: the duodenum, the jejunum, and the ileum. Small Intestine: Anatomy.
• Other digestive enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body’s constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes:
  • Phospholipids: ester bonds are hydrolyzed by phospholipase A₂
  • Cholesterol Cholesterol The principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils. Cholesterol Metabolism esters: ester bonds are hydrolyzed by cholesterol ester hydrolase Cholesterol ester hydrolase Cholesterol Metabolism
• Digestion Digestion Digestion refers to the process of the mechanical and chemical breakdown of food into smaller particles, which can then be absorbed and utilized by the body. Digestion and Absorption occurs until these lipids Lipids Lipids are a diverse group of hydrophobic organic molecules, which include fats, oils, sterols, and waxes. Fatty Acids and Lipids are broken down into FAs (or other small lipid molecules) which can be absorbed by the intestine.
• Also needed for digestion Digestion Digestion refers to the process of the mechanical and chemical breakdown of food into smaller particles, which can then be absorbed and utilized by the body. Digestion and Absorption of lipids Lipids Lipids are a diverse group of hydrophobic organic molecules, which include fats, oils, sterols, and waxes. Fatty Acids and Lipids:
  • Bile Bile An emulsifying agent produced in the liver and secreted into the duodenum. Its composition includes bile acids and salts; cholesterol; and electrolytes. It aids digestion of fats in the duodenum. Gallbladder and Biliary Tract: Anatomy salts for emulsification Emulsification Gastrointestinal Secretions (form smaller fat droplets Droplets Varicella-Zoster Virus/Chickenpox, allowing the water-soluble lipases more surface area to digest lipids Lipids Lipids are a diverse group of hydrophobic organic molecules, which include fats, oils, sterols, and waxes. Fatty Acids and Lipids)
  • Colipases: necessary coenzymes Coenzymes Small molecules that are required for the catalytic function of enzymes. Many vitamins are coenzymes. Basics of Enzymes of lipases

Micelles Micelles Particles consisting of aggregates of molecules held loosely together by secondary bonds. The surface of micelles are usually comprised of amphiphatic compounds that are oriented in a way that minimizes the energy of interaction between the micelle and its environment. Liquids that contain large numbers of suspended micelles are referred to as emulsions. Malabsorption and Maldigestion

As lipids Lipids Lipids are a diverse group of hydrophobic organic molecules, which include fats, oils, sterols, and waxes. Fatty Acids and Lipids are broken down, they (along with components from the bile Bile An emulsifying agent produced in the liver and secreted into the duodenum. Its composition includes bile acids and salts; cholesterol; and electrolytes. It aids digestion of fats in the duodenum. Gallbladder and Biliary Tract: Anatomy) arrange themselves in structures called micelles Micelles Particles consisting of aggregates of molecules held loosely together by secondary bonds. The surface of micelles are usually comprised of amphiphatic compounds that are oriented in a way that minimizes the energy of interaction between the micelle and its environment. Liquids that contain large numbers of suspended micelles are referred to as emulsions. Malabsorption and Maldigestion.

• Micelles Micelles Particles consisting of aggregates of molecules held loosely together by secondary bonds. The surface of micelles are usually comprised of amphiphatic compounds that are oriented in a way that minimizes the energy of interaction between the micelle and its environment. Liquids that contain large numbers of suspended micelles are referred to as emulsions. Malabsorption and Maldigestion are tiny spherical droplets Droplets Varicella-Zoster Virus/Chickenpox:
  • Interior portion is lipophilic
  • Exterior portion is hydrophilic Hydrophilic Aminoglycosides 
  • Surrounded by phospholipids from bile Bile An emulsifying agent produced in the liver and secreted into the duodenum. Its composition includes bile acids and salts; cholesterol; and electrolytes. It aids digestion of fats in the duodenum. Gallbladder and Biliary Tract: Anatomy
• Contain all fat soluble components to be absorbed:
  • Free fatty acids Acids Chemical compounds which yield hydrogen ions or protons when dissolved in water, whose hydrogen can be replaced by metals or basic radicals, or which react with bases to form salts and water (neutralization). An extension of the term includes substances dissolved in media other than water. Acid-Base Balance
  • Monoacylglycerides
  • Cholesterol Cholesterol The principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils. Cholesterol Metabolism
  • Phospholipids
  • Fat soluble vitamins: A, D, E, and K
• Bring the lipid components up to the enterocyte walls for absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption

Absorption of Lipids

Location

• Majority of absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption occurs in the small intestine Small intestine The small intestine is the longest part of the GI tract, extending from the pyloric orifice of the stomach to the ileocecal junction. The small intestine is the major organ responsible for chemical digestion and absorption of nutrients. It is divided into 3 segments: the duodenum, the jejunum, and the ileum. Small Intestine: Anatomy.
• Short-chain fatty acids Short-chain fatty acids Digestion and Absorption may be absorbed in the stomach Stomach The stomach is a muscular sac in the upper left portion of the abdomen that plays a critical role in digestion. The stomach develops from the foregut and connects the esophagus with the duodenum. Structurally, the stomach is C-shaped and forms a greater and lesser curvature and is divided grossly into regions: the cardia, fundus, body, and pylorus. Stomach: Anatomy.

Long-chain fatty acids Long-chain fatty acids Digestion and Absorption

• Mixed micelles Micelles Particles consisting of aggregates of molecules held loosely together by secondary bonds. The surface of micelles are usually comprised of amphiphatic compounds that are oriented in a way that minimizes the energy of interaction between the micelle and its environment. Liquids that contain large numbers of suspended micelles are referred to as emulsions. Malabsorption and Maldigestion are formed and approach the brush border Brush border Tubular System of the enterocytes:
  • pH pH The quantitative measurement of the acidity or basicity of a solution. Acid-Base Balance change breaks the micelles Micelles Particles consisting of aggregates of molecules held loosely together by secondary bonds. The surface of micelles are usually comprised of amphiphatic compounds that are oriented in a way that minimizes the energy of interaction between the micelle and its environment. Liquids that contain large numbers of suspended micelles are referred to as emulsions. Malabsorption and Maldigestion down, releasing their “cargo” (e.g., long-chain fatty acids Long-chain fatty acids Digestion and Absorption ( LCFAs LCFAs Digestion and Absorption), cholesterol Cholesterol The principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils. Cholesterol Metabolism, etc ETC The electron transport chain (ETC) sends electrons through a series of proteins, which generate an electrochemical proton gradient that produces energy in the form of adenosine triphosphate (ATP). Electron Transport Chain (ETC).).
  • The lipids Lipids Lipids are a diverse group of hydrophobic organic molecules, which include fats, oils, sterols, and waxes. Fatty Acids and Lipids (in the immediate proximity of the enterocytes) are now able to be absorbed.
• The lipids Lipids Lipids are a diverse group of hydrophobic organic molecules, which include fats, oils, sterols, and waxes. Fatty Acids and Lipids travel directly across the membrane to enter the cytosol Cytosol A cell’s cytoskeleton is a network of intracellular protein fibers that provides structural support, anchors organelles, and aids intra- and extracellular movement. The Cell: Cytosol and Cytoskeleton of epithelial cells.
• Activation: 
  • Takes place at the cytosolic side of the outer mitochondrial membrane
  • Acetate coenzyme A (acyl-CoA) synthetase forms activated FA FA Inhaled Anesthetics.
• Esterification: 
  • Takes place in the endoplasmic reticulum Endoplasmic reticulum A system of cisternae in the cytoplasm of many cells. In places the endoplasmic reticulum is continuous with the plasma membrane (cell membrane) or outer membrane of the nuclear envelope. If the outer surfaces of the endoplasmic reticulum membranes are coated with ribosomes, the endoplasmic reticulum is said to be rough-surfaced; otherwise it is said to be smooth-surfaced. The Cell: Organelles (ER)
  • TAGs are resynthesized from free fatty acids Acids Chemical compounds which yield hydrogen ions or protons when dissolved in water, whose hydrogen can be replaced by metals or basic radicals, or which react with bases to form salts and water (neutralization). An extension of the term includes substances dissolved in media other than water. Acid-Base Balance (FFAs) via esterification.
• In the Golgi apparatus, fats Fats The glyceryl esters of a fatty acid, or of a mixture of fatty acids. They are generally odorless, colorless, and tasteless if pure, but they may be flavored according to origin. Fats are insoluble in water, soluble in most organic solvents. They occur in animal and vegetable tissue and are generally obtained by boiling or by extraction under pressure. They are important in the diet (dietary fats) as a source of energy. Energy Homeostasis are repackaged as chylomicrons 
• Chylomicrons:
  • Structure: TAGs (and some cholesterol Cholesterol The principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils. Cholesterol Metabolism) are coated with a film of phospholipids and proteins Proteins Linear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein. Energy Homeostasis forming small droplets Droplets Varicella-Zoster Virus/Chickenpox (hydrophobic inside; hydrophilic Hydrophilic Aminoglycosides outside)
  • Exit the enterocyte on its basolateral side and enter the lymphatic circulation Circulation The movement of the blood as it is pumped through the cardiovascular system. ABCDE Assessment → thoracic duct Thoracic Duct The largest lymphatic vessel that passes through the chest and drains into the subclavian vein. Lymphatic Drainage System: Anatomy → left subclavian vein

Short-chain fatty acids Short-chain fatty acids Digestion and Absorption ( SCFAs SCFAs Digestion and Absorption) to medium-chain fatty acids Medium-chain fatty acids Digestion and Absorption ( MCFAs MCFAs Digestion and Absorption)

• In the small intestine Small intestine The small intestine is the longest part of the GI tract, extending from the pyloric orifice of the stomach to the ileocecal junction. The small intestine is the major organ responsible for chemical digestion and absorption of nutrients. It is divided into 3 segments: the duodenum, the jejunum, and the ileum. Small Intestine: Anatomy:
  • SCFAs SCFAs Digestion and Absorption and MCFAs MCFAs Digestion and Absorption travel across the enterocyte without assistance.
  • Absorbed into venous circulation Circulation The movement of the blood as it is pumped through the cardiovascular system. ABCDE Assessment → hepatic portal Hepatic portal Liver: Anatomy vein → liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy
• In the large intestine Large intestine The large intestines constitute the last portion of the digestive system. The large intestine consists of the cecum, appendix, colon (with ascending, transverse, descending, and sigmoid segments), rectum, and anal canal. The primary function of the colon is to remove water and compact the stool prior to expulsion from the body via the rectum and anal canal. Colon, Cecum, and Appendix: Anatomy ( SCFAs SCFAs Digestion and Absorption use the SMCT1 transporter):
  • Na⁺/SCFA cotransporter located in the apical membrane
  • Uses the sodium Sodium A member of the alkali group of metals. It has the atomic symbol na, atomic number 11, and atomic weight 23. Hyponatremia gradient generated by the basolateral Na⁺/K⁺ pump Pump ACES and RUSH: Resuscitation Ultrasound Protocols
  • The pump Pump ACES and RUSH: Resuscitation Ultrasound Protocols also assists in the absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption of water in the large intestine Large intestine The large intestines constitute the last portion of the digestive system. The large intestine consists of the cecum, appendix, colon (with ascending, transverse, descending, and sigmoid segments), rectum, and anal canal. The primary function of the colon is to remove water and compact the stool prior to expulsion from the body via the rectum and anal canal. Colon, Cecum, and Appendix: Anatomy

Transport of Lipids

Transport

• Lipids Lipids Lipids are a diverse group of hydrophobic organic molecules, which include fats, oils, sterols, and waxes. Fatty Acids and Lipids are hydrophobic → require transport proteins Transport proteins Proteins and Peptides (lipoproteins):
  • Lipoproteins are amphipathic, complex spherical structures that can travel through the blood while carrying lipid.
  • Structure: consists of a hydrophobic core and a hydrophilic Hydrophilic Aminoglycosides shell of varying lipids Lipids Lipids are a diverse group of hydrophobic organic molecules, which include fats, oils, sterols, and waxes. Fatty Acids and Lipids
  • 5 types of lipoproteins (based on internal lipid content and apolipoproteins in the shell):
    • Chylomicrons: carry dietary lipids Lipids Lipids are a diverse group of hydrophobic organic molecules, which include fats, oils, sterols, and waxes. Fatty Acids and Lipids
    • VLDLs: carry triglyceride
    • LDLs: carry cholesterol Cholesterol The principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils. Cholesterol Metabolism
    • HDLs: carry phospholipids and cholesterol Cholesterol The principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils. Cholesterol Metabolism
• Free fatty acids Acids Chemical compounds which yield hydrogen ions or protons when dissolved in water, whose hydrogen can be replaced by metals or basic radicals, or which react with bases to form salts and water (neutralization). An extension of the term includes substances dissolved in media other than water. Acid-Base Balance (FFAs) are transported by albumin Albumin Serum albumin from humans. It is an essential carrier of both endogenous substances, such as fatty acids and bilirubin, and of xenobiotics in the blood. Liver Function Tests:
  • Albumin Albumin Serum albumin from humans. It is an essential carrier of both endogenous substances, such as fatty acids and bilirubin, and of xenobiotics in the blood. Liver Function Tests has approximately 7 binding sites for FAs.
  • Albumin Albumin Serum albumin from humans. It is an essential carrier of both endogenous substances, such as fatty acids and bilirubin, and of xenobiotics in the blood. Liver Function Tests may facilitate uptake of FAs in organs in need of FFAs.

Lipoproteins and their composition

Lipid Synthesis (Lipogenesis)

Lipogenesis Lipogenesis De novo fat synthesis in the body. This includes the synthetic processes of fatty acids and subsequent triglycerides in the liver and the adipose tissue. Lipogenesis is regulated by numerous factors, including nutritional, hormonal, and genetic elements. Nonalcoholic Fatty Liver Disease is the process of synthesizing new lipids Lipids Lipids are a diverse group of hydrophobic organic molecules, which include fats, oils, sterols, and waxes. Fatty Acids and Lipids. This occurs primarily in the liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy, but also throughout the body.

Fatty acid synthesis Synthesis Polymerase Chain Reaction (PCR)

FA FA Inhaled Anesthetics synthesis Synthesis Polymerase Chain Reaction (PCR) occurs in the cytosol Cytosol A cell’s cytoskeleton is a network of intracellular protein fibers that provides structural support, anchors organelles, and aids intra- and extracellular movement. The Cell: Cytosol and Cytoskeleton via several enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body’s constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes which are all contained in a single complex known as fatty acid synthase. 

In the cytoplasm:

• Acetyl-CoA Acetyl-CoA Acetyl CoA participates in the biosynthesis of fatty acids and sterols, in the oxidation of fatty acids and in the metabolism of many amino acids. It also acts as a biological acetylating agent. Citric Acid Cycle carboxylase adds a carboxyl group to some acetyl-CoA Acetyl-CoA Acetyl CoA participates in the biosynthesis of fatty acids and sterols, in the oxidation of fatty acids and in the metabolism of many amino acids. It also acts as a biological acetylating agent. Citric Acid Cycle → generates malonyl-CoA
  • The only regulated step in fatty acid synthesis Synthesis Polymerase Chain Reaction (PCR)
  • The only enzyme in the process separate from the fatty acid synthase
• In the fatty acid synthase (enzymatic complex):
  • Step 1: Transacylases replace the CoA on acetyl-CoA Acetyl-CoA Acetyl CoA participates in the biosynthesis of fatty acids and sterols, in the oxidation of fatty acids and in the metabolism of many amino acids. It also acts as a biological acetylating agent. Citric Acid Cycle and malonyl-CoA with acyl-carrier proteins Proteins Linear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein. Energy Homeostasis (ACP)
    • Fatty acid synthase contains an ACP binding site, which holds the molecule in place during the subsequent reactions
  • Step 2: Synthase enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body’s constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes join the 2 carbon acetyl-ACP with the 3 carbon malonyl-ACP
    • Releases a CO₂ in the process → forms a 4 carbon chain bound to ACP
    • This molecule has a ketone group at carbon 3
  • Step 3: A reductase enzyme reduce this ketone to a hydroxyl (OH^–) group (uses NADPH NADPH Nicotinamide adenine dinucleotide phosphate. A coenzyme composed of ribosylnicotinamide 5′-phosphate (nmn) coupled by pyrophosphate linkage to the 5′-phosphate adenosine 2. Pentose Phosphate Pathway → NADP)
  • Step 4: A dehydrase enzyme catalyze the removal of water (the OH^– group from carbon 3 and an additional H⁺ from carbon 2) → generates a trans-2,3 double bond
  • Step 5: A reductase enzyme reduces the double bond to a single bond (uses NADPH NADPH Nicotinamide adenine dinucleotide phosphate. A coenzyme composed of ribosylnicotinamide 5′-phosphate (nmn) coupled by pyrophosphate linkage to the 5′-phosphate adenosine 2. Pentose Phosphate Pathway → NADP) 
  • Additional 2-carbon units from malonyl-ACP are added to the growing chain until the chain has 16 carbons (palmitoyl-ACP)
  • Thioesterase Thioesterase Fatty Acid Metabolism cleaves the ACP off palmitoyl-ACP → generates palmitic acid Palmitic acid A common saturated fatty acid found in fats and waxes including olive oil, palm oil, and body lipids. Fatty Acids and Lipids (end of synthesis Synthesis Polymerase Chain Reaction (PCR) in the cytoplasm)
• FAs are initially synthesized in a saturated form.

In the endoplasmic reticulum Endoplasmic reticulum A system of cisternae in the cytoplasm of many cells. In places the endoplasmic reticulum is continuous with the plasma membrane (cell membrane) or outer membrane of the nuclear envelope. If the outer surfaces of the endoplasmic reticulum membranes are coated with ribosomes, the endoplasmic reticulum is said to be rough-surfaced; otherwise it is said to be smooth-surfaced. The Cell: Organelles:

• Elongation Elongation Polymerase Chain Reaction (PCR) beyond 16 carbons:
  • Catalyzed by elongase enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body’s constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes (not part of a complex)
  • Malonyl-CoA is used to add 2 carbons at a time to the growing chain
• Desaturation:
  • Catalyzed by desaturase enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body’s constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes (which are named according to the location of the double bonds they create)
  • Humans have Δ5, Δ6, and Δ9 desaturases → FA FA Inhaled Anesthetics with double bonds beyond Δ9 (e.g., linoleic acid Linoleic acid A doubly unsaturated fatty acid, occurring widely in plant glycosides. It is an essential fatty acid in mammalian nutrition and is used in the biosynthesis of prostaglandins and cell membranes. Fatty Acids and Lipids [Δ9,12]) are considered essential fatty acids Essential fatty acids Long chain organic acid molecules that must be obtained from the diet. Examples are linoleic acids and linolenic acids. Fatty Acids and Lipids, and must be obtained from the diet

Triacylglycerol and glycerophosphoipid synthesis Synthesis Polymerase Chain Reaction (PCR)

Acyltransferases join free fatty acids Acids Chemical compounds which yield hydrogen ions or protons when dissolved in water, whose hydrogen can be replaced by metals or basic radicals, or which react with bases to form salts and water (neutralization). An extension of the term includes substances dissolved in media other than water. Acid-Base Balance (FFAs) to a glycerol backbone by creating ester bonds to create both TAGs and glycerophospholipids Glycerophospholipids Derivatives of phosphatidic acid in which the hydrophobic regions are composed of two fatty acids and a polar alcohol is joined to the c-3 position of glycerol through a phosphodiester bond. They are named according to their polar head groups, such as phosphatidylcholine and phosphatidylethanolamine. Fatty Acids and Lipids. These reactions result in the loss of an H₂O molecule.

Common pathway Common pathway Hemostasis:

• Both TAGs and glycerophospholipids Glycerophospholipids Derivatives of phosphatidic acid in which the hydrophobic regions are composed of two fatty acids and a polar alcohol is joined to the c-3 position of glycerol through a phosphodiester bond. They are named according to their polar head groups, such as phosphatidylcholine and phosphatidylethanolamine. Fatty Acids and Lipids starts with glycerol-3-phosphate
• Glycerol-3-phosphate + FA FA Inhaled Anesthetics₁ → lysophosphatidic acid
  • Catalyzed by acyltransferase 1
  • FA FA Inhaled Anesthetics₁ is usually saturated
• Lysophosphatidic acid + FA FA Inhaled Anesthetics₂ → phosphatidic acid
  • Catalyzed by acyltransferase 2
  • FA FA Inhaled Anesthetics₂ is usually unsaturated
• Phosphatidic acid is then further metabolized to make TAGs and phospholipids

To make a TAG:

• HPO₄^3- is removed from phosphatidic acid by phosphatase → leaves diacylglycerol Diacylglycerol Second Messengers ( DAG DAG Second Messengers) molecule (glycerol with 2 FAs attached via ester bonds)
• DAG DAG Second Messengers + FA FA Inhaled Anesthetics₃ → TAG
  • Catalyzed by acyltransferase 3
  • TAG = a fat or oil

To make a glycerophospholipid:

• Two different general mechanisms:
  • Both involve the creation of high-energy intermediates
  • The energy in these intermediates is used to catalyze the addition of the unique R group
• Mechanism 1: 
  • Phosphatidic acid is activated by cytidine triphosphate ( CTP CTP Purine and Pyrimidine Metabolism) → cytidine monophosphate (CMP) is released and replaced by the R group
  • E.g., Phosphatidic acid + CTP CTP Purine and Pyrimidine Metabolism → cytidine diphosphate (CDP)-DAG, which reacts with inositol → forms phosphatidylinositol + CMP
• Mechanism 2: 
  • R group is activated by ATP and CTP CTP Purine and Pyrimidine Metabolism, then added to DAG DAG Second Messengers
  • E.g., Ethanolamine + ATP → phosphorylethanolamine + ADP → add CTP CTP Purine and Pyrimidine Metabolism → CDP-ethanolamine + PP_i → add DAG DAG Second Messengers → phosphatidylethanolamine + CMP

Sphingolipid synthesis Synthesis Polymerase Chain Reaction (PCR)

• Sphingolipids Sphingolipids A class of membrane lipids that have a polar head and two nonpolar tails. They are composed of one molecule of the long-chain amino alcohol sphingosine (4-sphinganine) or one of its derivatives, one molecule of a long-chain acid, a polar head alcohol and sometimes phosphoric acid in diester linkage at the polar head group. Fatty Acids and Lipids are comprised of:
  • Sphingosine
  • 1 Fatty acid
  • 1 R group
• Generating the ceramide backbone: 
  • Serine Serine A non-essential amino acid occurring in natural form as the l-isomer. It is synthesized from glycine or threonine. It is involved in the biosynthesis of purines; pyrimidines; and other amino acids. Synthesis of Nonessential Amino Acids + palmitoyl-CoA → dihydrosphingosine
  • A fatty acid is added to the dihydrosphingosine → generates the ceramide backbone
• Several molecules can bind BIND Hyperbilirubinemia of the Newborn to the ceramide, producing molecules with different functions:
  • Sphingomyelins:
    • Ceramide + a phosphate group Phosphate group Nucleic Acids + choline
    • Found in the myelin sheath of nerve cells
  • Cerebrosides:
    • Ceramide + monosaccharide (a single sugar)
    • Important components of nerve cell membranes
  • Gangliosides:
    • Ceramide + complex carbohydrate
    • Important role in modulating membrane proteins Proteins Linear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein. Energy Homeostasis, ion channels Channels The Cell: Cell Membrane, and cell signaling

Cholesterol Cholesterol The principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils. Cholesterol Metabolism synthesis Synthesis Polymerase Chain Reaction (PCR)

• 3 molecules of acetyl-CoA Acetyl-CoA Acetyl CoA participates in the biosynthesis of fatty acids and sterols, in the oxidation of fatty acids and in the metabolism of many amino acids. It also acts as a biological acetylating agent. Citric Acid Cycle are joined together to form 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA)
• HMG-CoA reductase HMG-CoA reductase Enzymes that catalyze the reversible reduction of alpha-carboxyl group of 3-hydroxy-3-methylglutaryl-coenzyme A to yield mevalonic acid. Cholesterol Metabolism:
  • Converts HMG-CoA into mevalonate Mevalonate Cholesterol Metabolism 
  • Rate-limiting step in cholesterol Cholesterol The principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils. Cholesterol Metabolism synthesis Synthesis Polymerase Chain Reaction (PCR)
  • HMG-CoA reductase HMG-CoA reductase Enzymes that catalyze the reversible reduction of alpha-carboxyl group of 3-hydroxy-3-methylglutaryl-coenzyme A to yield mevalonic acid. Cholesterol Metabolism is the enzyme inhibited by statin drugs 
• Mevalonate Mevalonate Cholesterol Metabolism is converted into activated isoprenes (5-carbon molecules)
• Isoprenes are combined to form the 30-carbon molecule squalene Squalene A natural 30-carbon triterpene. Cholesterol Metabolism
• Squalene Squalene A natural 30-carbon triterpene. Cholesterol Metabolism is folded into the 4-ring structure called lanosterol Lanosterol A triterpene that derives from the chair-boat-chair-boat folding of 2, 3-oxidosqualene. It is metabolized to cholesterol and cucurbitacins. Cholesterol Metabolism, which resembles cholesterol Cholesterol The principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils. Cholesterol Metabolism
• An energy-dependent process converts lanosterol Lanosterol A triterpene that derives from the chair-boat-chair-boat folding of 2, 3-oxidosqualene. It is metabolized to cholesterol and cucurbitacins. Cholesterol Metabolism to cholesterol Cholesterol The principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils. Cholesterol Metabolism via multiple additional enzymatic steps

Lipid Breakdown (Lipolysis)

Lipolysis Lipolysis The metabolic process of breaking down lipids to release free fatty acids, the major oxidative fuel for the body. Lipolysis may involve dietary lipids in the digestive tract, circulating lipids in the blood, and stored lipids in the adipose tissue or the liver. A number of enzymes are involved in such lipid hydrolysis, such as lipase and lipoprotein lipase from various tissues. Nonalcoholic Fatty Liver Disease is the process of breaking down lipids Lipids Lipids are a diverse group of hydrophobic organic molecules, which include fats, oils, sterols, and waxes. Fatty Acids and Lipids.

Lipolysis Lipolysis The metabolic process of breaking down lipids to release free fatty acids, the major oxidative fuel for the body. Lipolysis may involve dietary lipids in the digestive tract, circulating lipids in the blood, and stored lipids in the adipose tissue or the liver. A number of enzymes are involved in such lipid hydrolysis, such as lipase and lipoprotein lipase from various tissues. Nonalcoholic Fatty Liver Disease of TAGs

There is a different lipase Lipase An enzyme of the hydrolase class that catalyzes the reaction of triacylglycerol and water to yield diacylglycerol and a fatty acid anion. It is produced by glands on the tongue and by the pancreas and initiates the digestion of dietary fats. Malabsorption and Maldigestion for each of the three ester bonds in a TAG. The lipases cleave off fatty acids Acids Chemical compounds which yield hydrogen ions or protons when dissolved in water, whose hydrogen can be replaced by metals or basic radicals, or which react with bases to form salts and water (neutralization). An extension of the term includes substances dissolved in media other than water. Acid-Base Balance by adding an H₂O molecule to the ester bond (a hydrolysis Hydrolysis The process of cleaving a chemical compound by the addition of a molecule of water. Proteins and Peptides reaction).

• Hormone-sensitive lipase Lipase An enzyme of the hydrolase class that catalyzes the reaction of triacylglycerol and water to yield diacylglycerol and a fatty acid anion. It is produced by glands on the tongue and by the pancreas and initiates the digestion of dietary fats. Malabsorption and Maldigestion cleaves off FA FA Inhaled Anesthetics₁ → generates diacylglycerol Diacylglycerol Second Messengers ( DAG DAG Second Messengers) + free FA FA Inhaled Anesthetics₁
  • Stimulated by epinephrine Epinephrine The active sympathomimetic hormone from the adrenal medulla. It stimulates both the alpha- and beta- adrenergic systems, causes systemic vasoconstriction and gastrointestinal relaxation, stimulates the heart, and dilates bronchi and cerebral vessels. Sympathomimetic Drugs (which also stimulates glycogen breakdown and gluconeogenesis Gluconeogenesis Gluconeogenesis is the process of making glucose from noncarbohydrate precursors. This metabolic pathway is more than just a reversal of glycolysis. Gluconeogenesis provides the body with glucose not obtained from food, such as during a fasting period. The production of glucose is critical for organs and cells that cannot use fat for fuel. Gluconeogenesis)
  • Inhibited by insulin Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. Insulin
• DAG DAG Second Messengers lipase Lipase An enzyme of the hydrolase class that catalyzes the reaction of triacylglycerol and water to yield diacylglycerol and a fatty acid anion. It is produced by glands on the tongue and by the pancreas and initiates the digestion of dietary fats. Malabsorption and Maldigestion cleaves off FA FA Inhaled Anesthetics₂ → generates monoacylglycerol (MAG) + free FA FA Inhaled Anesthetics₂
• MAG lipase Lipase An enzyme of the hydrolase class that catalyzes the reaction of triacylglycerol and water to yield diacylglycerol and a fatty acid anion. It is produced by glands on the tongue and by the pancreas and initiates the digestion of dietary fats. Malabsorption and Maldigestion cleaves off FA FA Inhaled Anesthetics ₃ → generates glycerol + free FA FA Inhaled Anesthetics₃

These lipases are found in adipocytes Adipocytes Cells in the body that store fats, usually in the form of triglycerides. White adipocytes are the predominant type and found mostly in the abdominal cavity and subcutaneous tissue. Brown adipocytes are thermogenic cells that can be found in newborns of some species and hibernating mammals. Adipose Tissue: Histology and lysosomes Lysosomes A class of morphologically heterogeneous cytoplasmic particles in animal and plant tissues characterized by their content of hydrolytic enzymes and the structure-linked latency of these enzymes. The intracellular functions of lysosomes depend on their lytic potential. The single unit membrane of the lysosome acts as a barrier between the enzymes enclosed in the lysosome and the external substrate. The activity of the enzymes contained in lysosomes is limited or nil unless the vesicle in which they are enclosed is ruptured or undergoes membrane fusion. The Cell: Organelles.

Fatty acid beta oxidation Beta oxidation Fatty Acid Metabolism

• FA FA Inhaled Anesthetics β oxidation is the process by which individual FAs are broken down to generate energy. 
• Occurs in the mitochondria Mitochondria Semiautonomous, self-reproducing organelles that occur in the cytoplasm of all cells of most, but not all, eukaryotes. Each mitochondrion is surrounded by a double limiting membrane. The inner membrane is highly invaginated, and its projections are called cristae. Mitochondria are the sites of the reactions of oxidative phosphorylation, which result in the formation of ATP. They contain distinctive ribosomes, transfer RNAs; amino Acyl tRNA synthetases; and elongation and termination factors. Mitochondria depend upon genes within the nucleus of the cells in which they reside for many essential messenger RNAs. Mitochondria are believed to have arisen from aerobic bacteria that established a symbiotic relationship with primitive protoeukaryotes. The Cell: Organelles and peroxisomes Peroxisomes Microbodies which occur in animal and plant cells and in certain fungi and protozoa. They contain peroxidase, catalase, and allied enzymes. The Cell: Organelles of target cells
• Generates more ATP per carbon than sugars do. 
• Process overview:
  • Activation via the addition of coenzyme A (CoA) → generates fatty acyl-CoA
  • Transport into the mitochondria Mitochondria Semiautonomous, self-reproducing organelles that occur in the cytoplasm of all cells of most, but not all, eukaryotes. Each mitochondrion is surrounded by a double limiting membrane. The inner membrane is highly invaginated, and its projections are called cristae. Mitochondria are the sites of the reactions of oxidative phosphorylation, which result in the formation of ATP. They contain distinctive ribosomes, transfer RNAs; amino Acyl tRNA synthetases; and elongation and termination factors. Mitochondria depend upon genes within the nucleus of the cells in which they reside for many essential messenger RNAs. Mitochondria are believed to have arisen from aerobic bacteria that established a symbiotic relationship with primitive protoeukaryotes. The Cell: Organelles (long chain FAs requires carnitine Carnitine A constituent of striated muscle and liver. It is an amino acid derivative and an essential cofactor for fatty acid metabolism. Fatty Acid Metabolism)
  • A dehydrogenase removes hydrogen molecules from carbons 2 and 3 (the α and β carbons, respectively) creating a trans-2,3, double bond
    • FAD + 2H⁺ (removed by dehydrogenase) → FADH₂ (used to generate ATP)
  • A hydratase adds water to the double bond, creating an -OH group on carbon 3
  • Another dehydrogenase removes hydrogens from the -OH group and carbon 3 (oxidation of the β carbon), creating a ketone on carbon 3
    • NAD NAD+ A coenzyme composed of ribosylnicotinamide 5′-diphosphate coupled to adenosine 5′-phosphate by pyrophosphate linkage. It is found widely in nature and is involved in numerous enzymatic reactions in which it serves as an electron carrier by being alternately oxidized (NAD+) and reduced (NADH). Pentose Phosphate Pathway⁺ + 2H⁺ (removed by dehydrogenase) → NADH (used to generate ATP) + 1H⁺
  • Thiolase Thiolase Fatty Acid Metabolism enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body’s constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes cleave off the first 2 carbons (an acetyl-CoA Acetyl-CoA Acetyl CoA participates in the biosynthesis of fatty acids and sterols, in the oxidation of fatty acids and in the metabolism of many amino acids. It also acts as a biological acetylating agent. Citric Acid Cycle) and add a new CoA to the remaining chain (which is now 2 carbons shorter than the original) 
• Net: each palmitoyl CoA Palmitoyl CoA A fatty acid coenzyme derivative which plays a key role in fatty acid oxidation and biosynthesis. Fatty Acid Metabolism (16-carbon FA FA Inhaled Anesthetics chain) produces/uses:
  • 2 ATP used for activation 
  • 7 FADH₂ → 10.5 ATP (1.5 ATP per FADH₂)
  • 7 NADH → 17.5 ATP (2.5 ATP per NADH)
  • 8 acetyl-CoA Acetyl-CoA Acetyl CoA participates in the biosynthesis of fatty acids and sterols, in the oxidation of fatty acids and in the metabolism of many amino acids. It also acts as a biological acetylating agent. Citric Acid Cycle → 80 ATP (via citric acid cycle Cycle The type of signal that ends the inspiratory phase delivered by the ventilator Invasive Mechanical Ventilation)
  • Total: 108 ATP (yield: 106 ATP)

Clinical Relevance

• Familial hypercholesterolemia Familial hypercholesterolemia Lipid Disorders: caused by a mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations in 1 of several critical enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body’s constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes involved in the breakdown of LDLs, causing their accumulation in plasma Plasma The residual portion of blood that is left after removal of blood cells by centrifugation without prior blood coagulation. Transfusion Products. A predisposition for early-onset atherosclerotic cardiovascular disease results.
• Nonalcoholic fatty liver Nonalcoholic fatty liver Fatty liver finding without excessive alcohol consumption. Nonalcoholic Fatty Liver Disease disease: caused by the accumulation of lipids Lipids Lipids are a diverse group of hydrophobic organic molecules, which include fats, oils, sterols, and waxes. Fatty Acids and Lipids ( triacylglycerols Triacylglycerols Fatty Acids and Lipids) in the liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy. If the accumulation is chronic, causing inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body’s defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation, nonalcoholic steatohepatitis Nonalcoholic Steatohepatitis Nonalcoholic Fatty Liver Disease develops.
• Hyperchylomicronemia: significantly elevated triglycerides Triglycerides Fatty Acids and Lipids and chylomicrons due to an autosomal recessive Autosomal recessive Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal recessive diseases are only expressed when 2 copies of the recessive allele are inherited. Autosomal Recessive and Autosomal Dominant Inheritance mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations in lipoprotein lipase Lipase An enzyme of the hydrolase class that catalyzes the reaction of triacylglycerol and water to yield diacylglycerol and a fatty acid anion. It is produced by glands on the tongue and by the pancreas and initiates the digestion of dietary fats. Malabsorption and Maldigestion. Presentation may be with xanthomas Xanthomas Lipid Disorders, hepatosplenomegaly Hepatosplenomegaly Cytomegalovirus, recurrent abdominal pain Abdominal Pain Acute Abdomen, and pancreatitis Pancreatitis Inflammation of the pancreas. Pancreatitis is classified as acute unless there are computed tomographic or endoscopic retrograde cholangiopancreatographic findings of chronic pancreatitis. The two most common forms of acute pancreatitis are alcoholic pancreatitis and gallstone pancreatitis. Acute Pancreatitis.