title: Hyperinsulinemia Enhances Hepatic Expression of the Fatty Acid Transporter Cd36 and Provokes Hepatosteatosis and Hepatic Insulin Resistance.
abstract: Hepatosteatosis is associated with the development of both hepatic insulin resistance and Type 2 diabetes. Hepatic expression of Cd36, a fatty acid transporter, is enhanced in obese and diabetic murine models and human nonalcoholic fatty liver disease, and thus it correlates with hyperinsulinemia, steatosis, and insulin resistance. Here, we have explored the effect of hyperinsulinemia on hepatic Cd36 expression, development of hepatosteatosis, insulin resistance, and dysglycemia. A 3-week sucrose-enriched diet was sufficient to provoke hyperinsulinemia, hepatosteatosis, hepatic insulin resistance, and dysglycemia in CBA/J mice. The development of hepatic steatosis and insulin resistance in CBA/J mice on a sucrose-enriched diet was paralleled by increased hepatic expression of the transcription factor Pparγ and its target gene Cd36 whereas that of genes implicated in lipogenesis, fatty acid oxidation, and VLDL secretion was unaltered. Additionally, we demonstrate that insulin, in a Pparγ-dependent manner, is sufficient to directly increase Cd36 expression in perfused livers and isolated hepatocytes. Mouse strains that display low insulin levels, i.e. C57BL6/J, and/or lack hepatic Pparγ, i.e. C3H/HeN, do not develop hepatic steatosis, insulin resistance, or dysglycemia on a sucrose-enriched diet, suggesting that elevated insulin levels, via enhanced CD36 expression, provoke fatty liver development that in turn leads to hepatic insulin resistance and dysglycemia. Thus, our data provide evidence for a direct role for hyperinsulinemia in stimulating hepatic Cd36 expression and thus the development of hepatosteatosis, hepatic insulin resistance, and dysglycemia.
authors.affiliation: From the Umeå Centre for Molecular Medicine and.
authors.forename: Pär
authors.initials: P
authors.lastname: Steneberg
authors.affiliation: From the Umeå Centre for Molecular Medicine and.
authors.forename: Alexandros G
authors.initials: AG
authors.lastname: Sykaras
authors.affiliation: From the Umeå Centre for Molecular Medicine and.
authors.forename: Fredrik
authors.initials: F
authors.lastname: Backlund
authors.affiliation: From the Umeå Centre for Molecular Medicine and.
authors.forename: Jurate
authors.initials: J
authors.lastname: Straseviciene
authors.affiliation: the Department of Public Health and Clinical Medicine, Umeå University, SE-901 87 Umeå, Sweden.
authors.forename: Ingegerd
authors.initials: I
authors.lastname: Söderström
authors.affiliation: From the Umeå Centre for Molecular Medicine and helena.edlund@umu.se.
authors.forename: Helena
authors.initials: H
authors.lastname: Edlund
mesh_terms: D000818:Animals; D018955:CD36 Antigens / Q000235:genetics / Q000378:metabolism*; D005234:Fatty Liver / Q000209:etiology / Q000378:metabolism*; D056945:Hep G2 Cells; D006801:Humans; D007328:Insulin / Q000502:physiology; D007333:Insulin Resistance; D008099:Liver / Q000378:metabolism*; D008297:Male; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D047495:PPAR gamma / Q000378:metabolism
chemical_list: D018955:CD36 Antigens; D007328:Insulin; D047495:PPAR gamma
keywords: CD36; PPARγ; Type 2 diabetes; fatty acid transport; fatty liver; hepatocyte; insulin; insulin resistance