Mechanisms Linking the Metabolic Syndrome and Cardiovascular Disease: Role of Hepatic Insulin Resistance

Abstract

The worldwide prevalence of insulin resistant states such as the metabolic syndrome has grown rapidly over the past few decades. The metabolic syndrome is a constellation of common metabolic disorders that promote the development of atherosclerosis and cardiovascular disease. Studies in both human and animal models suggest that hepatic inflammation and insulin resistance are key initiating factors in the development of the metabolic syndrome. Chronic inflammation is known to be associated with visceral obesity and is characterized by production of abnormal adipokines and cytokines such as tumor necrosis factor a, interleukin-1 (IL-1), IL-6, leptin, and resistin. These factors inhibit insulin signaling in the liver (hepatocytes) by activating suppressors of cytokine signalling proteins; several kinases such as c-Jun N-terminal kinases, IKK-β, and Protein kinase C; and protein tyrosine phosphatase 1B, that in turn impair insulin signaling at insulin receptor and insulin receptor substrate level. Hepatic insulin resistance in turn causes impaired suppression of glucose production by insulin in hepatocytes leading to hyperglycemia, induction of very low density lipoprotein production, and de novo lipogenesis. Increased production of C-reactive protein (CRP) and plasminogen activator inhibitor-1, both markers of an inflammatory state, is also observed in insulin resistance. All of the above metabolic abnormalities can directly or indirectly promote atherosclerosis. In particular, hyperglycemia induces endothelial dysfunction, cellular proliferation, changes in extracellular matrix conformation, and impairment of low density lipoproteins (LDL)-receptor-mediated lipoprotein uptake. Small dense LDLs have higher affinity to the intimal proteoglycans, leading to the penetration of more LDL particles into the arterial wall. CRP can also accelerate atherosclerosis by increasing the expression of PAI-1 and adhesion molecules in endothelialcells, inhibition of nitric oxide formation, and increasing LDL uptake into macrophages. In summary, hepatic insulin resistance is a critical early event that underlies the development of the metabolic syndrome and progression to atherosclerosis and cardiovascular disease.