Complex Lipids & Cholesterol Biochemistry Flashcards
Sources of cholesterol
- Diet: consume ~300-600 mg/day
- Half is absorbed
- De novo synthesis: ~1gm/day
- Mostly in liver (highly regulated process)
General steps of de novo cholesterol synthesis
In hepatocyte cytoplasm:
Acetyl CoA (thiolase & HMG CoA synthase) –> HMG CoA (HMG CoA reductase*) + NADPH –> NADPH –> mevalonate –> lots of complicated steps resulting in key intermediates geranyl pyrophosphate and farnesyl pyrophosphate –> cholesterol
*key regulated step, rate limiting
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Key regulated step in cholesterol synthesis
HMG CoA (HMG CoA reductase*) + NADPH –> mevalonate
Primary means for controlling intracellular cholesterol levels
4 levels of HMG CoA reductase regulation
- Transcriptional regulation
- Translational regulation
- Regulation of degradation
- Regulation of phosphorylation
Key features of glycerophospholipids, sphingomyelin, glycosphingolipids (general)
- All lipids begin with glycerol or ceramide (sphingosine) backbone
- Polar head group:
- Phosphate linked to alcohol: glycerophospholipid
- Phosphate linked to choline: sphingomyelin
- Sugar moiety: glycosphingolipids
**Sphingolipids have no glycerol backbone - instead sphingosine with nitrogen in it
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Synthesis of different glycerophospholipids
- Backbone comes from phosphatidic acid (precursor in triglyceride biosynthesis)
- Head group added:
- Phosphatidylserine (PS)
- Phosphatidylethanolamine (PE)
- Head group formed de novo or from diet, activated by CDP then attached to backbone
- Phosphatidylcholine (PC)
- Head group formed de novo or from diet, activated by CDP then attached to backbone
- Another synthesis pathway: “base exchange”
- Head groups exchanged onto previously synthesized phospholipids
Important functions of sphingomyelin
- Major structural lipid in nerve tissue
Important functions of phosphatidylinositol
- Important in signal transduction
- Reservoir for arachidonic acid
- Important in membrane protein anchoring
Important functions of phosphatidylcholine
- Lung surfactant
- Reservoir of choline
- Present in bile
- Most abundant phospholipid in body
Synthesis of arachidonic acid
Made from dietary linoleic acid
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Synthesis of prostaglandins
Synthesized from arachidonic acid by COX
Fates of cholesterol
- Steroid hormones
- Bile acids
- Secrete 300-600mg of cholesterol in bile salts/day
- Component of membranes
- Vitamin D
Transcriptional regulation of HMG-CoA reductase
- Cholesterol present in excess –> HMG CoA reductase gene transcribed 20x less
- Insulin/glucagon regulate via transcription
- Insulin increases expression of enzyme (high in fed state when NADPH is high)
- Glucagon decreases expression
Translational regulation of HMG-CoA reductase
- Cholesterol present in excess –> translation rate of coding mRNA 5x less than in absence of cholesterol
- mRNA half-life decreases with excess cholesterol
Regulation of degradation of HMG-CoA reductase
- In excess cholesterol –> half-life of HMG-CoA reductase decreases from 11 hours to 2 hours