Selective Hepatic Insulin Resistance, VLDL Overproduction, and Hypertriglyceridemia

Abstract

A central feature of metabolic syndrome is hepatic hypersecretion of very low-density lipoprotein (VLDL), which results in hypertriglyceridemia (HTG), a consistent finding associated with obesity and type 2 diabetes mellitus. Under physiological conditions, insulin signaling regulates VLDL production by targeting apolipoprotein (apo) B for degradation and limiting apoB synthesis.1 Pancreatic release of insulin into the portal vein after eating reduces VLDL output during the postprandial period allowing for transient triglyceride (TG) storage for future secretion. This is consistent with insulin acting as an anabolic hormone stimulating energy storage in both liver and fat. Because of reduced hepatic secretion of VLDL, there is less competition for lipolysis with intestinal lipoproteins resulting in their preferential clearance. Loss of this acute pathway may be the earliest consequence of overnutrition and with it is the loss of the cyclical nature of VLDL production during the postprandial transition. There is then continuous secretion of VLDL and packaging of excess TG into larger sized (VLDL1) and more numerous VLDL particles, inducing HTG. Insulin induction of de novo lipogenesis (DNL) favors TG synthesis and occurs independent of effects on apoB. With insulin resistance, more apoB is available and along with stimulation of DNL, there is hypersecretion of VLDL1. In classical forms of insulin resistance, transcriptional effects increase VLDL production and occur with enhanced gluconeogenesis and forkhead box O1 (FoxO1) activity.2-4 Sustained nuclear localization of FoxO1 increases expression of microsomal triglyceride transfer protein (MTP) 4 and apolipoprotein C-III (apoC-III) 5 resulting in substantial increases in VLDL production above and beyond loss of acute VLDL regulation.2 This review summarizes current understanding of insulin action and insulin resistance related to the complex relationships of apoB and TG in formation of VLDL. This article accompanies the ATVB in Focus: New Developments in Hepatic LipoproteinProduction and Clinical Relevance series that was published in the May 2012 issue. VLDL Assembly and Hepatic VLDL OverproductionVLDL assembly is initiated by the synthesis of B100 (Figure 1), a 550 kDa protein or its shorter form, B48, the protein product of edited apoB mRNA. Editing is a process that introduces a stop codon in the apoB transcript, and in humans this occurs in the intestine. In other species, including mouse and rat, liver makes Abstract-Insulin plays a central role in regulating energy metabolism, including hepatic transport of very low-density lipoprotein (VLDL)-associated triglyceride. Hepatic hypersecretion of VLDL and consequent hypertriglyceridemia leads to lower circulating high-density lipoprotein levels and generation of small dense low-density lipoproteins characteristic of the dyslipidemia commonly observed in metabolic syndrome and type 2 diabetes mellitus. Physiological fluctuations of insulin modulate VLDL secretion, and insulin inhibition of VLDL secretion upon...

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