Biochemistry HSCI 3030 001 Chapter 12 - Lipid Metabolism

Importance: Key energy sources for many cells. Most fatty acids are obtained through diet in animals.
Digestion: Triacylglycerols (TAGs) are digested in the small intestine by pancreatic lipase, producing fatty acids and monoacylglycerol.
Transport and Conversion: Monoacylglycerols are transported across the plasma membrane of intestinal wall cells and converted back into triacylglycerols.
- Fatty acids may be:
- Converted to triacylglycerols based on current energy needs.
- Degraded for energy generation.
- Used for membrane synthesis.
Hormonal Regulation:
- High serum glucose levels post-meal stimulate insulin release, promoting TAG formation in adipose tissues.
- Under low glucose conditions, various hormones stimulate TAG degradation into glycerol and fatty acids.

Definition: The synthesis of triacylglycerols, known as lipogenesis.
Process: Uses glycerol-3-phosphate or dihydroxyacetone phosphate reacting with three molecules of Acyl-CoA (fatty acid esters of CoASH).
Acyl-CoA Synthesization:
$R-C-O + ext{ATP} + ext{CoASH} <br /> ightarrow R-C-S- ext{CoA} + ext{Ppi} + ext{AMP}$
Formation of Phosphatidic Acid: Through two sequential acylation of glycerol-3-phosphate or direct acylation of dihydroxyacetone phosphate.
Conversion Steps:
1. Phosphatidic acid converts to diacylglycerol catalyzed by Phosphatidic acid phosphatase.
2. A final acylation results in triacylglycerol synthesis.
Sources of Fatty Acids: Derived from diet and de novo synthesis.

Key Enzymes:
- Glycerol kinase (found in liver): Converts glycerol to glycerol-3-phosphate.
- Dihydroxyacetone phosphate acyltransferase: Acts in ER or peroxisomes.
- Acyltransferases: Involved in various acylation steps leading to the formation of phospholipids and triacylglycerols.
Process Visualization: Figure 10.2 illustrates the enzymes involved in triacylglycerol synthesis from glycerol-3-phosphate and acyl-CoA esters.

Definition: The metabolic process that breaks down stored fat under low energy conditions.
Triggers: Occurs during fasting, vigorous exercise, and stress responses.
Hormonal Activation: Hormones like glucagon and epinephrine bind to adipocyte plasma membrane receptors, activating lipase enzymes through cAMP synthesis.
End Products: Fatty acids and glycerol are released into the bloodstream.
- Glycerol transports to the liver for conversion into glucose or lipids.
- Fatty acids bind to serum albumin and are oxidized in various tissues for energy.
Fatty Acid Degradation: Most fatty acids undergo beta-oxidation to produce Acetyl-CoA in mitochondria.
- Non-standard fatty acids are oxidized through alpha-oxidation in different pathways.

Overview: Occurs primarily in mitochondria. Activation of fatty acids occurs before beta-oxidation begins.
Activation: Reaction with ATP and CoASH catalyzed by Acyl CoA ligase in the mitochondrial outer membrane.
Transport: Since mitochondrial inner membranes are impermeable to Acyl-CoA, they attach to carnitine for transport to the matrix.
Oxidation Steps:
1. First Reaction: Catalyzed by acyl-CoA dehydrogenase, $( ext{producing FADH}_2)$ which enters the electron transport chain (ETC).
2. Second Reaction: Enoyl-CoA is hydrated by enoyl-CoA hydrase yielding L-beta-hydroxyacyl-CoA.
3. Third Reaction: Oxidation of L-beta-hydroxyacyl-CoA to beta-ketoacyl-CoA yielding NADH.
4. Final Step: Thiolytic cleavage releases Acetyl-CoA and returns Acyl-CoA, continuing the process until two Acetyl-CoA molecules are formed.

Definition: Products of excess Acetyl-CoA formed during fatty acid oxidation; include acetoacetate, beta-hydroxybutyrate, and acetone, produced via ketogenesis.
Ketogenesis Process:
1. Condensation of two Acetyl-CoA molecules to form acetoacetyl-CoA.
2. Further condensation with another Acetyl-CoA yields HMG-CoA.
3. Cleavage of HMG-CoA produces Acetyl-CoA and acetoacetate.
4. Acetoacetate can reduce to beta-hydroxybutyrate or decarboxylate to form acetone.
Clinical Relevance: Ketosis is observed in uncontrolled diabetes, and during prolonged starvation, brain cells utilize ketone bodies for energy.

Sources: Cholesterol is derived from dietary intake and synthesized de novo by the body; synthesis is suppressed when adequate dietary cholesterol is available.
Synthesis Locations: While all tissues can produce cholesterol, the liver is the primary site of synthesis.
Stages of Cholesterol Biosynthesis:
1. Formation of HMG-CoA from Acetyl-CoA.
2. Conversion of HMG-CoA to squalene.
3. Final conversion of squalene to cholesterol.
First Phase Similarity: Identical to the ketosis pathway until HMG-CoA formation.
Reduction: HMG-CoA reduces to mevalonate, catalyzed by HMG-CoA reductase using NADPH.
Intermediate Reactions: Involves cytoplasmic reactions converting mevalonate to farnesylpyrophosphate and then to squalene, the latter requiring NADPH.

Enzymatic Steps:
- Squalene monooxygenase and 2,3-oxidosqualene lanosterol cyclase transform squalene into lanosterol.
- Lanosterol undergoes multiple transformations aided by NADPH and oxygen to yield 7-Dehydrocholesterol, which is ultimately reduced to cholesterol.
Cholesterol Function: Acts as a precursor for steroid hormones and bile salts.

Mechanism: Cholesterol and steroids cannot be degraded into smaller molecules but can be derivatized into bile acids, which are synthesized from cholesterol in the liver.
Bile Acid Roles: Enhance dietary fat absorption; emulsifying agents breaking large lipid droplets into smaller ones; assist in forming biliary micelles for fat and fat-soluble vitamins (A, D, E, and K) absorption.