1 Role of Liver In Triglyceride Role of Liver In Triglyceride Homeostasis Homeostasis Larry L. Swift, Ph.D. Department of Pathology Vanderbilt University School of Medicine Metabolic Syndrome Metabolic Syndrome • Abdominal obesity • Atherogenic dyslipidemia • Elevated blood pressure Elevated blood pressure • Insulin resistance • Prothrombotic state • Proinflammatory state Metabolic Syndrome Dyslipidemia Metabolic Syndrome Dyslipidemia • Elevated plasma triglycerides • Decreased HDL cholesterol N ll l f LDL hl t l idi • Normal levels of LDL cholesterol carried in small dense particles • Lipoprotein alterations contribute to increased risk for CHD What are the metabolic alterations underlying these changes in plasma lipoproteins? Overproduction of VLDL What are the mechanisms underlying VLDL overproduction?
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Role of Liver In Triglyceride Role of Liver In Triglyceride HomeostasisHomeostasis
Larry L. Swift, Ph.D.Department of Pathology
Vanderbilt University School of Medicine
Metabolic SyndromeMetabolic Syndrome
• Abdominal obesity • Atherogenic dyslipidemia • Elevated blood pressureElevated blood pressure• Insulin resistance• Prothrombotic state • Proinflammatory state
• Source of triglyceride for lipoproteinsA bl f t i l id i h li t i• Assembly of triglyceride-rich lipoproteins
• Triglyceride-rich lipoprotein catabolism• Effects of insulin resistance on triglyceride-
rich lipoprotein production• VLDL secretion and fatty liver
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Assembly of TriglycerideAssembly of Triglyceride--Rich Rich LipoproteinsLipoproteins
• Complex process requiring coordination of lipid and protein synthesisProcess is constit ti e in nat re b t can be• Process is constitutive in nature, but can be modulated by variety of factors
• Assembly and secretion of TG-rich lipoproteins are absolutely dependent on the ability of the cell to synthesize apoB and the presence of MTP
Assembly of TriglycerideAssembly of Triglyceride--Rich Rich LipoproteinsLipoproteins
G. Shelness
Microsomal Triglyceride Transfer Microsomal Triglyceride Transfer Protein (MTP)Protein (MTP)
• A heterodimeric protein complex consisting of 97 kDa subunit and protein disulfide isomerase (PDI)
• Located in the lumen of the endoplasmic reticulum (ER)
• Facilitates lipid transfer and is essential for assembly of VLDL by the liver
• Inhibition of MTP leads to reduction in plasma triglycerides and cholesterol
Assembly of TriglycerideAssembly of Triglyceride--Rich Rich LipoproteinsLipoproteins
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Targets for Regulation of VLDL AssemblyTargets for Regulation of VLDL Assembly
G.F. Gibbons, G.F. Gibbons, et alet al., ., Biochem Soc TransBiochem Soc Trans 3232: 59: 59--64, 200464, 2004
Points of Regulation of VLDL Points of Regulation of VLDL ProductionProduction
• Substrate availabilityA B d d ti b t l d• Apo B degradation by proteasomal and non proteasomal (insulin dependent) pathways
• Source of triglyceride for lipoproteinsA bl f t i l id i h li t i• Assembly of triglyceride-rich lipoproteins
• Triglyceride-rich lipoprotein catabolism• Effects of insulin resistance on triglyceride-
rich lipoprotein production• VLDL secretion and fatty liver
Effects of Insulin Resistance on TGEffects of Insulin Resistance on TG--Rich Lipoprotein ProductionRich Lipoprotein Production
• Increased fatty acid flux from adipose tissue to the liverIncreased hepatic ptake of VLDL IDL and• Increased hepatic uptake of VLDL, IDL, and chylomicron remnants
• Increased de novo lipogenesis• Decreased degradation of apoB• Increased activity of MTP
Increased Fatty Acid Flux from Increased Fatty Acid Flux from Adipose Tissue to the LiverAdipose Tissue to the Liver
• Insulin stimulates adipocyte fatty acid uptake and inhibits fatty acid release (HSL) leading to decreased plasma NEFAto decreased plasma NEFA
• Insulin resistance leads to increased mobilization of fatty acids from adipose tissue and increased plasma NEFA
Substrate SourcesSubstrate Sources for the Assembly for the Assembly of ApoBof ApoB--LipoproteinsLipoproteins
Ginsberg et al., Arch. Med. Res. 36: 232, 2005
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De Novo LipogenesisDe Novo Lipogenesis
• Hepatic insulin resistance leads to upregulation of sterol regulatory element-binding protein-1 (SREBP-1c) and activates lipogenic enzymes
• Carbohydrate response element binding• Carbohydrate response element-binding protein (ChREBP) regulates expression of key glucose-responsive genes of lipogenesis
• Synergistic action of SREBP-1c and ChREBP directs conversion of excess glucose to fatty acids and enhances esterification
Decreased Degradation of ApoBDecreased Degradation of ApoB
• Insulin regulates degradation of apoB through PI3-kinase pathway
• Insulin resistance leads to decreased apoB degradation and increased secretion
Increased MTP ActivityIncreased MTP Activity
• Mttp gene has insulin response element in the promoter
• In human liver cells Mttp gene expression is negatively regulated by insulin through thenegatively regulated by insulin through the MAPK cascade
• Increased MTP mRNA is associated with enhanced synthesis of VLDL in wild-type animals and in animal models of insulin resistance
Increased MTP ActivityIncreased MTP Activity
• Forkhead box 01 (Fox01) has been shown to mediate inhibitory action of insulin on target gene expression
• Fox01 stimulates hepatic MTP expression; p pthe effect is counteracted by insulin
• Fox01 gain-of-function is associated with enhanced MTP expression, augmented hepatic VLDL production, and elevated plasma TG levels in Fox01 transgenic mice
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Insulin Signaling through Fox01Insulin Signaling through Fox01
Kamagate et al. J. Clin. Invest. 118: 234702364, 2008
Hepatic VLDL Assembly and SecretionHepatic VLDL Assembly and Secretion
Sparks and Sparks, J. Clin. Invest. 118: 2012-2015, 2008