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

• Published in: Journal of hepatology Vol. 47; no. 1; pp. 142 - 156
• Main Authors: Leclercq, Isabelle A., Da Silva Morais, Alain, Schroyen, Ben, Van Hul, Noémi, Geerts, Albert
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier B.V 01.07.2007; Elsevier
• Subjects: Atherosclerosis (general aspects, experimental research); Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Diabetes. Impaired glucose tolerance; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Gastroenterology and Hepatology; Hepatocytes - metabolism; Hepatocytes - pathology; Humans; Insulin Resistance; Liver - metabolism; Liver - pathology; Medical sciences; Metabolic diseases; Metabolic Syndrome - metabolism; Metabolic Syndrome - pathology; Miscellaneous; Other metabolic disorders; Stem Cells - metabolism; Stem Cells - pathology; FFA; JNK; GSK-3; IKKβ; IRS; PKD1; TNF; NF-κB; PI3K; PPAR; VLDL; KC; HSC; NAFLD/NASH; AGE; IL; PEPCK; PKB; IR; PKC; SOCS; RAGE; MAPK; SREBP-1c; ECM; MCD; SEC; ChREBP; ROS; AMPK; FAS; PIP3; GLUT4; LPC; ERK; sterol regulatory element-binding protein-1c; non-alcoholic fatty liver disease/non-alcoholic steatohepatitis; receptor of advanced glycation end-products; AMP-dependent kinase; hepatic stellate cells; phosphatidylinositol-3-kinase; nuclear factor-kappa B; Inhibitory kappa B kinase beta; fatty acid synthase; very low density lipoprotein; phosphoenol-pyruvate carboxy-kinase; tumor necrosis factor α; Kupffer cells; free fatty acids; advanced glycation end-products; mitogen-activated protein kinase; glycogen synthase kinase-3; reactive oxygen species; sinusoidal endothelial cells; insulin receptor substrate; peroxisome proliferator-activated receptor; interleukin; c-Jun-N-terminal kinase; protein kinase C; protein kinase B; Phosphatidylinositol (3,4,5) triphosphate; suppressor of cytokine signaling; carbohydrate regulatory element-binding protein; phosphoinositide-dependent protein kinase; liver progenitor cells; extracellular regulated kinase; methionine and choline-deficient; glucose transporter-4; insulin receptor; extracellular matrix; Endocrinopathy; Type 2 diabetes; Hyperinsulinemia; Oxidative stress; Hepatic sinusoid; Liver; Cardiovascular disease; Hepatic disease; Metabolic diseases; Insulin; Mechanism; Vascular disease; Resistance; Cirrhosis; Hepatocyte; X Syndrome; Non alcoholic steatohepatitis; Atherosclerosis; Digestive diseases
• ISSN: 0168-8278; 1600-0641
• DOI: 10.1016/j.jhep.2007.04.002

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.