title: The lipogenic transcription factor ChREBP dissociates hepatic steatosis from             insulin resistance in mice and humans.
abstract: Nonalcoholic fatty liver disease (NAFLD) is associated with all features of the             metabolic syndrome. Although deposition of excess triglycerides within liver cells, a             hallmark of NAFLD, is associated with a loss of insulin sensitivity, it is not clear             which cellular abnormality arises first. We have explored this in mice overexpressing             carbohydrate responsive element-binding protein (ChREBP). On a standard             diet, mice overexpressing ChREBP remained insulin sensitive, despite increased             expression of genes involved in lipogenesis/fatty acid esterification and resultant             hepatic steatosis (simple fatty liver). Lipidomic analysis revealed that the steatosis             was associated with increased accumulation of monounsaturated fatty acids (MUFAs). In             primary cultures of mouse hepatocytes, ChREBP overexpression induced expression of             stearoyl-CoA desaturase 1 (Scd1), the enzyme responsible for the conversion of saturated             fatty acids (SFAs) into MUFAs. SFA impairment of insulin-responsive Akt phosphorylation             was therefore rescued by the elevation of Scd1 levels upon ChREBP overexpression,             whereas pharmacological or shRNA-mediated reduction of Scd1 activity decreased the             beneficial effect of ChREBP on Akt phosphorylation. Importantly, ChREBP-overexpressing             mice fed a high-fat diet showed normal insulin levels and improved insulin signaling and             glucose tolerance compared with controls, despite having greater hepatic steatosis.             Finally, ChREBP expression in liver biopsies from patients with nonalcoholic             steatohepatitis was increased when steatosis was greater than 50% and decreased in the             presence of severe insulin resistance. Together, these results demonstrate that             increased ChREBP can dissociate hepatic steatosis from insulin resistance, with             beneficial effects on both glucose and lipid metabolism.
authors.affiliation: INSERM, U1016, Institut Cochin, Paris, France.
authors.forename: Fadila
authors.initials: F
authors.lastname: Benhamed
authors.forename: Pierre-Damien
authors.initials: PD
authors.lastname: Denechaud
authors.forename: Maud
authors.initials: M
authors.lastname: Lemoine
authors.forename: Céline
authors.initials: C
authors.lastname: Robichon
authors.forename: Marthe
authors.initials: M
authors.lastname: Moldes
authors.forename: Justine
authors.initials: J
authors.lastname: Bertrand-Michel
authors.forename: Vlad
authors.initials: V
authors.lastname: Ratziu
authors.forename: Lawrence
authors.initials: L
authors.lastname: Serfaty
authors.forename: Chantal
authors.initials: C
authors.lastname: Housset
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Capeau
authors.forename: Jean
authors.initials: J
authors.lastname: Girard
authors.forename: Hervé
authors.initials: H
authors.lastname: Guillou
authors.forename: Catherine
authors.initials: C
authors.lastname: Postic
mesh_terms: D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism*; D005229:Fatty Acids, Monounsaturated / Q000378:metabolism*; D005234:Fatty Liver / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D007333:Insulin Resistance; D050155:Lipogenesis; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008297:Male; D024821:Metabolic Syndrome / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D065626:Non-alcoholic Fatty Liver Disease; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D013230:Stearoyl-CoA Desaturase / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D005229:Fatty Acids, Monounsaturated; C116385:MLXIPL protein, human; C506001:Mlxipl protein, mouse; D009687:Nuclear Proteins; D014157:Transcription Factors; C523776:SCD1 protein, human; C490333:Scd1 protein, mouse; D013230:Stearoyl-CoA Desaturase; D051057:Proto-Oncogene Proteins c-akt