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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

Lipid Homeostasis and Transport

CH353 February 12, 2008

summary
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
cholesteryl ester synthesis
in liver

acyl-CoA-cholesterol acyl transferase (ACAT)

outside cells (on HDLs)

lecithin-cholesterol acyl transferase (LCAT)

+

Cholesteryl Ester Synthesis
triacylglycerol biosynthesis
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)
lipoproteins
Structure of Low-Density Lipoprotein (LDL)

Electron microscope images of lipoproteins

Lipoproteins
chylomicrons
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
very low density lipoprotein vldl
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
low density lipoprotein ldl
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
high density lipoprotein hdl
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
systemic transport of lipid and lipoprotein
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

receptor mediated cholesterol endocytosis
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
cell membrane transport proteins
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
reverse cholesterol transport
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
regulation of hmg coa reductase
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
regulation of sterol biosynthetic genes
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
cholesterol regulation of transcription and protein turnover of hmg coa
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

transcription of lipid biosynthetic enzymes regulated by srebp
Transcription of Lipid Biosynthetic Enzymes Regulated by SREBP

from Horton, Goldstein, Brown (2002) J. Clin. Invest. 109:1125

regulation of cholesterol biosynthesis
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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