Biomaterials, Biodegradables and Biomimetics Research Group

Review Paper

Insulin resistance in hepatocytes and sinusoidal liver cells: Mechanisms and consequences

Abstract

Hepatic insulin resistance is an important underlying cause of the metabolic syndrome that manifests itself in diseases such as diabetes type II, atherosclerosis or non-alcoholic fatty liver disease (NAFLD). In this paper, we summarize comprehensively the current state of knowledge pertaining to the molecular mechanisms that lead to insulin resistance in hepatocytes and sinusoidal liver cells. In hepatocytes, the insulin resistant state is brought about by at least one, but more likely by a combination, of the following pathological alterations: hyperglycaemia and hyperinsulinaemia, formation of advanced glycation end-products, increased free fatty acids and their metabolites, oxidative stress and altered profiles of adipocytokines. Insulin resistance in hepatocytes distorts directly glucose metabolism, especially the control over glucose output into the circulation and interferes with cell survival and proliferation, while hepatic fatty acid synthesis remains stimulated by compensatory hyperinsulinaemia, resulting in steatosis. Very few studies have addressed insulin resistance in sinusoidal liver cells. These cells are not simply bystanders and passive witnesses of the changes affecting the hepatocytes. They are target cells that will respond to the pathological alterations occurring in the insulin resistant state. They are also effector cells that may exacerbate insulin resistance in hepatocytes by increasing oxidative stress and by secreting cytokines such as TNF and IL-6. Moreover, activation of sinusoidal endothelial cells, Kupffer cells and stellate cells will lead to chemo-attraction of inflammatory cells. Finally, activation of stellate cells will set in motion a fibrogenic response that paves the way to cirrhosis.

Journal
Journal of Hepatology
Volume
47
Issue
1
Pagination
142-156
URL
http://ac.els-cdn.com/S0168827807002103/1-s2.0-S0168827807002103-main.pdf?_tid=578d5476-0ffc-11e3-8deb-00000aab0f02&acdnat=1377706402_c363d78bb7ab2d48e44278490b5fc914
Keywords
Liver, Insulin resistance
Rights
Open Access
Peer Reviewed
Yes
Status
published
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