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Lipid Homeostasis and Transport

Lipid Homeostasis and Transport. CH353 February 12, 2008. Summary. Major transported forms of lipids Cholesterol esters Triacylglycerols (triglycerides) Lipid transport particles (solubilize lipids & target cells) Chylomicrons (dietary triglyceride transport)

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Lipid Homeostasis and Transport

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  1. Lipid Homeostasis and Transport CH353 February 12, 2008

  2. Summary • Major transported forms of lipids • Cholesterol esters • Triacylglycerols (triglycerides) • Lipid transport particles (solubilize lipids & target cells) • Chylomicrons (dietary triglyceride transport) • VLDL (hepatic lipid transport) • LDL (cholesterol transport and regulation) • HDL (reverse cholesterol transport) • Cholesterol Homeostasis • Intracellular transport • Regulation of enzyme levels • Regulation of enzyme activity

  3. in liver acyl-CoA-cholesterol acyl transferase (ACAT) outside cells (on HDLs) lecithin-cholesterol acyl transferase (LCAT) + Cholesteryl Ester Synthesis

  4. Triacylglycerol Biosynthesis • Synthesis of triacylglycerol from phosphatidic acid • Common precursor with membrane glycerolipid biosynthesis • Mainly in liver and intestine (for transport) and adipose tissue (for storage)

  5. Structure of Low-Density Lipoprotein (LDL) Electron microscope images of lipoproteins Lipoproteins

  6. Chylomicrons • Density: < 1.006 g/ml • Mass: 50–1000 x 103 kDa • Diameter: 75–1200 nm • Composition: • 2% protein (apoB-48, apoA, apoC, apoE) • 9% phospholipids, 85% triglycerides, 4% cholesterol • Origin: intestinal enterocytes (apoproteins and lipid) • Function: Transports dietary triglycerides from intestine to tissues; returns remnants to liver

  7. Very Low Density Lipoprotein (VLDL) • Density: < 0.95–1.006 g/ml • Mass: 10–80 x 103 kDa • Diameter: 30–80 nm • Composition: • 10% protein (apoB-100, apoC, apoE) • 20% phospholipids, 50% triglycerides, 20% cholesterol • Origin: hepatocytes (apolipoproteins and lipid) • Function: Transports hepatic triglycerides to tissues; is converted into LDL

  8. Low Density Lipoprotein (LDL) • Density: 1.006–1.063 g/ml • Mass: 2.3 x 103 kDa • Diameter: 18–25 nm • Composition: • 25% protein (apoB-100) • 20% phospholipids, 10% triglycerides, 45% cholesterol • Origin: derived from VLDL (by loss of triglycerides) • Function: major carrier of cholesterol to liver and other tissues; regulates cholesterol biosynthesis by LDL receptor-mediated endocytosis

  9. High Density Lipoprotein (HDL) • Density: 1.063–1.210 g/ml • Mass: 0.175–0.360 x 103 kDa • Diameter: 5–12 nm • Composition: • 55% protein (apoA) • 25% phospholipids, 5% triglycerides, 15% cholesterol • Origin: pre-HDL secreted by hepatocytes • Function: Loads cholesterol from tissues and delivers it to liver, steroidogenic tissues and other lipoproteins; apoA-1 binds to SR-B1; can release cholesterol without endocytosis

  10. Systemic Transport of Lipid and Lipoprotein • Chylomicrons transport dietary lipid to tissues; endocytosis of remnants (apoB-48 or apoE) • VLDLs transport lipids from liver to tissues; remnants become LDLs or endocytosed by liver (apoB-100 or apoE) • LDLs transport cholesterol to liver and other tissues by endocytosis (apoB-100) • HDL precursors remove cholesterol from tissues; HDLs deliver cholesterol to the liver and other tissues (apoA) lipoprotein lipase regulated by apoC on lipoproteins

  11. Receptor-Mediated Cholesterol Endocytosis • Allows sensing of plasma cholesterol by producing cells • LDL endocytosis requires LDL receptor (binds apoB-100) • genetic deficiency of functional LDL receptors causes familial hypercholesterolemia • LRP (lipoprotein receptor-related protein) binds apoE in remnants of chylomicrons and VLDLs • Internalized cholesterol interacts with sensors on endoplasmic reticulum, regulating biosynthesis

  12. Cell Membrane Transport Proteins • ABC (ATP binding cassette) proteins transport cholesterol across cell membranes • ABCA1 ubiquitous transport of cholesterol and phospholipid into HDLs • deficiency causes Tangier’s disease • ABCG1 macrophage-specific transporter • Hepatic and intestinal ABCG5/8 export cholesterol and other sterols into bile and lumen, respectively • deficiency causes β-sitosterolemia

  13. Reverse Cholesterol Transport • Secreted ApoA forms pre-HDL by acquiring transported lipids • Cholesterol and phospholipid is transported across cell membrane by ABCA1 (and ABCG1) • Cholesterol is esterified by plasma lecithin-cholesterol acyl transferase (LCAT) using lecithin from the cell • Mature HDL binds to its receptor SRB1 on liver and steroidogenic cells, and delivers its cholesterol • Cholesterol can be transferred to other lipoproteins by cholesteryl ester-transfer protein

  14. Regulation of HMG-CoA Reductase Regulating amount of enzyme (200x) • Transcription: 8x ↑ mRNA levels • Translation: 5x ↑ protein synthesis • Protein turnover: 5x ↓ protein degradation Regulating activity of enzyme • by AMP-activated protein kinase • high [AMP] inhibits (phosphorylates) HMG-CoA reductase • by hormone-dependent kinases / phophatases • glucagon inhibits (phosphorylates) HMG-CoA reductase • insulin activates (dephosphorylates) HMG-CoA reductase

  15. Regulation of Sterol Biosynthetic Genes • Steroid Regulatory Element Binding Protein (SREBP) is retained in ER by SCAP (SREBP cleavage-activating protein) • Low cholesterol allows migration of SREBP from ER to golgi where it can be cleaved by 2 proteases • Cleavage of SREBP allows N-terminal fragment to enter nucleus and activate steroid biosynthetic genes

  16. Cholesterol Regulation of Transcription and Protein Turnover of HMG-CoA Abbreviations SRE: sterol response element (DNA sequence) SREBP: SRE binding protein (transcription factor) SCAP: SREBP cleavage-activating protein (SREBP chaperone) INSIG: Insulin-induced gene 1 protein (ER retention) SSD: sterol-sensing domain (5 membrane spanning helices) S1P: Site 1 protease S2P: Site 2 protease HMG-CoAR: HMG-CoA reductase LDLR: LDL receptor INSIG INSIG from Ikonen (2008) Nature Rev. Mol. Cell Biol. 9:125

  17. Transcription of Lipid Biosynthetic Enzymes Regulated by SREBP from Horton, Goldstein, Brown (2002) J. Clin. Invest. 109:1125

  18. Regulation of Cholesterol Biosynthesis • Hormones regulate the phosphorylation of HMG-CoA reductase: • Phosphorylated – Inactive • Dephosphorylated – Active • High intracellular cholesterol: • stimulates ACAT for cholesterol storage • lowers expression of LDL receptor gene

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