title: Salt-inducible kinase 2 links transcriptional coactivator p300 phosphorylation to the prevention of ChREBP-dependent hepatic steatosis in mice.
abstract: Obesity and type 2 diabetes are associated with increased lipogenesis in the liver. This results in fat accumulation in hepatocytes, a condition known as hepatic steatosis, which is a form of nonalcoholic fatty liver disease (NAFLD), the most common cause of liver dysfunction in the United States. Carbohydrate-responsive element-binding protein (ChREBP), a transcriptional activator of glycolytic and lipogenic genes, has emerged as a major player in the development of hepatic steatosis in mice. However, the molecular mechanisms enhancing its transcriptional activity remain largely unknown. In this study, we have identified the histone acetyltransferase (HAT) coactivator p300 and serine/threonine kinase salt-inducible kinase 2 (SIK2) as key upstream regulators of ChREBP activity. In cultured mouse hepatocytes, we showed that glucose-activated p300 acetylated ChREBP on Lys672 and increased its transcriptional activity by enhancing its recruitment to its target gene promoters. SIK2 inhibited p300 HAT activity by direct phosphorylation on Ser89, which in turn decreased ChREBP-mediated lipogenesis in hepatocytes and mice overexpressing SIK2. Moreover, both liver-specific SIK2 knockdown and p300 overexpression resulted in hepatic steatosis, insulin resistance, and inflammation, phenotypes reversed by SIK2/p300 co-overexpression. Finally, in mouse models of type 2 diabetes and obesity, low SIK2 activity was associated with increased p300 HAT activity, ChREBP hyperacetylation, and hepatic steatosis. Our findings suggest that inhibition of hepatic p300 activity may be beneficial for treating hepatic steatosis in obesity and type 2 diabetes and identify SIK2 activators and specific p300 inhibitors as potential targets for pharmaceutical intervention.
authors.affiliation: Institut Cochin, Département d'Endocrinologie, Métabolisme et Cancer, Université Paris Descartes, CNRS, UMR 8104, INSERM, U1016, Paris, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Bricambert
authors.forename: Jonatan
authors.initials: J
authors.lastname: Miranda
authors.forename: Fadila
authors.initials: F
authors.lastname: Benhamed
authors.forename: Jean
authors.initials: J
authors.lastname: Girard
authors.forename: Catherine
authors.initials: C
authors.lastname: Postic
authors.forename: Renaud
authors.initials: R
authors.lastname: Dentin
mesh_terms: D000107:Acetylation; D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D001665:Binding Sites / Q000235:genetics; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005227:Fatty Acids / Q000378:metabolism; D005234:Fatty Liver / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D055785:Gene Knockdown Techniques; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000209:etiology; D007333:Insulin Resistance; D051379:Mice; D008822:Mice, Transgenic; D065626:Non-alcoholic Fatty Liver Disease; D009687:Nuclear Proteins / Q000378:metabolism*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011770:Pyruvate Kinase / Q000235:genetics; D014157:Transcription Factors / Q000378:metabolism*; D050880:p300-CBP Transcription Factors / Q000737:chemistry / Q000378:metabolism*
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D005227:Fatty Acids; C506001:Mlxipl protein, mouse; D009687:Nuclear Proteins; D014157:Transcription Factors; D050880:p300-CBP Transcription Factors; C474808:salt-inducible kinase-2, mouse; D011770:Pyruvate Kinase; D017346:Protein Serine-Threonine Kinases