title: Cyp1b1 affects external control of mouse hepatocytes, fatty acid homeostasis and signaling involving HNF4α and PPARα.
abstract: Cytochrome P450 1b1 (Cyp1b1) is expressed in endothelia, stellate cells and pre-adipocytes, but not hepatocytes. Deletion alters liver fatty acid metabolism and prevents obesity and hepatic steatosis. This suggests a novel extra-hepatocyte regulation directed from cells that express Cyp1b1. To characterize these mechanisms, microarray gene expression was analyzed in livers of normal and congenic Cyp1b1-ko C57BL/6 J mice fed either low or high fat diets. Cyp1b1-ko gene responses indicate suppression of endogenous PPARα activity, a switch from triglyceride storage to mitochondrial fatty acid oxidation and decreased oxidative stress. Many gene responses in Cyp1b1-ko are sexually dimorphic and correspond to increased activity of growth hormone mediated by HNF4α. Male responses stimulated by GH pulses are enhanced, whereas responses that decline exhibit further suppression, including Cyp regulation by PPARα, CAR and PXR. These effects of Cyp1b1 deletion overlap with effects caused by deletion of the small heterodimeric partner, a suppressor of these nuclear factors. Redirection of gene expression associated with liver fat homeostasis in Cyp1b1-ko mice that directs hypothalamic control of GH and leptin. Cyp1b1-ko suppresses neonatal Scd1 and delays adult maturation of dimorphic GH/HNF4α signaling. Alternatively, deletion may diminish hypothalamic metabolism of estradiol, which establishes adult GH regulation.
authors.affiliation: Molecular and Environmental Toxicology Center, Endocrinology, University of Wisconsin, Madison, WI, 53706, United States; Reproductive Physiology Program, University of Wisconsin, Madison, WI, 53706, United States.
authors.forename: Justin R
authors.initials: JR
authors.lastname: Bushkofsky
authors.affiliation: Reproductive Physiology Program, University of Wisconsin, Madison, WI, 53706, United States.
authors.forename: Meghan
authors.initials: M
authors.lastname: Maguire
authors.affiliation: Department of Cell and Regenerative Biology, University of Wisconsin, Madison, WI, 53706, United States.
authors.forename: Michele Campaigne
authors.initials: MC
authors.lastname: Larsen
authors.affiliation: Department of Cell and Regenerative Biology, University of Wisconsin, Madison, WI, 53706, United States.
authors.forename: Yee Hoon
authors.initials: YH
authors.lastname: Fong
authors.affiliation: Molecular and Environmental Toxicology Center, Endocrinology, University of Wisconsin, Madison, WI, 53706, United States; Reproductive Physiology Program, University of Wisconsin, Madison, WI, 53706, United States; Department of Cell and Regenerative Biology, University of Wisconsin, Madison, WI, 53706, United States. Electronic address: jefcoate@wisc.edu.
authors.forename: Colin R
authors.initials: CR
authors.lastname: Jefcoate
mesh_terms: D000818:Animals; D065633:Cytochrome P-450 CYP1B1 / Q000235:genetics / Q000378:metabolism*; D005227:Fatty Acids / Q000235:genetics / Q000378:metabolism*; D005234:Fatty Liver / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005260:Female; D054439:Ghrelin / Q000235:genetics / Q000378:metabolism; D051557:Hepatocyte Nuclear Factor 4 / Q000235:genetics / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism* / Q000473:pathology; D006706:Homeostasis; D020738:Leptin / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009765:Obesity / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D047493:PPAR alpha / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013230:Stearoyl-CoA Desaturase / Q000235:genetics / Q000378:metabolism
chemical_list: D005227:Fatty Acids; D054439:Ghrelin; D051557:Hepatocyte Nuclear Factor 4; C496593:Hnf4a protein, mouse; D020738:Leptin; D047493:PPAR alpha; C585498:Cyp1b1 protein, mouse; D065633:Cytochrome P-450 CYP1B1; C490333:Scd1 protein, mouse; D013230:Stearoyl-CoA Desaturase
keywords: Cyp1b1; Growth hormone; HNF4α; Liver; Obesity; PPARα