title: HNF6 and Rev-erbα integrate hepatic lipid metabolism by overlapping and distinct transcriptional mechanisms.
abstract: Hepatocyte nuclear factor 6 (HNF6) is required for liver development, but its role in adult liver metabolism is not known. Here we show that deletion of HNF6 in livers of adult C57Bl/6 mice leads to hepatic steatosis in mice fed normal laboratory chow. Although HNF6 is known mainly as a transcriptional activator, hepatic loss of HNF6 up-regulated many lipogenic genes bound directly by HNF6. Many of these genes are targets of the circadian nuclear receptor Rev-erbα, and binding of Rev-erbα at these sites was lost when HNF6 was ablated in the liver. While HNF6 and Rev-erbα coordinately regulate hepatic lipid metabolism, each factor also affects additional gene sets independently. These findings highlight a novel mechanism of transcriptional repression by HNF6 and demonstrate how overlapping and distinct mechanisms of transcription factor function contribute to the integrated physiology of the liver.
authors.affiliation: Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA; The Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA; Department of Pharmacology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;
authors.forename: Yuxiang
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA; The Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;
authors.forename: Bin
authors.initials: B
authors.lastname: Fang
authors.affiliation: Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA; The Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;
authors.forename: Manashree
authors.initials: M
authors.lastname: Damle
authors.affiliation: Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA; The Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;
authors.forename: Dongyin
authors.initials: D
authors.lastname: Guan
authors.affiliation: Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA; The Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;
authors.forename: Zhenghui
authors.initials: Z
authors.lastname: Li
authors.affiliation: Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA; The Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;
authors.forename: Yong Hoon
authors.initials: YH
authors.lastname: Kim
authors.affiliation: Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA.
authors.forename: Maureen
authors.initials: M
authors.lastname: Gannon
authors.affiliation: Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA; The Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;
authors.forename: Mitchell A
authors.initials: MA
authors.lastname: Lazar
mesh_terms: D000818:Animals; D005234:Fatty Liver / Q000235:genetics; D017353:Gene Deletion; D005786:Gene Expression Regulation / Q000235:genetics*; D055786:Gene Knockout Techniques; D051559:Hepatocyte Nuclear Factor 6 / Q000235:genetics* / Q000378:metabolism*; D050356:Lipid Metabolism / Q000235:genetics*; D008099:Liver / Q000378:metabolism* / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1 / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding / Q000235:genetics
chemical_list: D051559:Hepatocyte Nuclear Factor 6; C498262:Nr1d1 protein, mouse; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1
keywords: HNF6; Onecut; Rev-erbα; integrative physiology; lipid metabolism; liver; steatosis