title: Cytochrome P450 1B1: An unexpected modulator of liver fatty acid homeostasis.
abstract: Cytochrome P450 1b1 (Cyp1b1) expression is absent in mouse hepatocytes, but present in liver endothelia and activated stellate cells. Increased expression during adipogenesis suggests a role of Cyp1b1 metabolism in fatty acid homeostasis. Wild-type C57BL/6j (WT) and Cyp1b1-null (Cyp1b1-ko) mice were provided low or high fat diets (LFD and HFD, respectively). Cyp1b1-deletion suppressed HFD-induced obesity, improved glucose tolerance and prevented liver steatosis. Suppression of lipid droplets in sinusoidal hepatocytes, concomitant with enhanced glycogen granules, was a consistent feature of Cyp1b1-ko mice. Cyp1b1 deletion altered the in vivo expression of 560 liver genes, including suppression of PPARγ, stearoyl CoA desaturase 1 (Scd1) and many genes stimulated by PPARα, each consistent with this switch in energy storage mechanism. Ligand activation of PPARα in Cyp1b1-ko mice by WY-14643 was, nevertheless, effective. Seventeen gene changes in Cyp1b1-ko mice correspond to mouse transgenic expression that attenuated diet-induced diabetes. The absence of Cyp1b1 in mouse hepatocytes indicates participation in energy homeostasis through extra-hepatocyte signaling. Extensive sexual dimorphism in hepatic gene expression suggests a developmental impact of estrogen metabolism by Cyp1b1. Suppression of Scd1 and increased leptin turnover support enhanced leptin participation from the hypothalamus. Cyp1b1-mediated effects on vascular cells may underlie these changes.
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: Molecular and Environmental Toxicology Center, University of Wisconsin, Madison, WI 53706, United States; Endocrinology and Reproductive Physiology Program, University of Wisconsin, Madison, WI 53706, United States.
authors.forename: Justin R
authors.initials: JR
authors.lastname: Bushkofsky
authors.affiliation: Department of Cell and Regenerative Biology, University of Wisconsin, Madison, WI 53706, United States.
authors.forename: Tyler
authors.initials: T
authors.lastname: Gorman
authors.affiliation: Department of Dermatology, University of Wisconsin, Madison, WI 53706, United States.
authors.forename: Vaqar
authors.initials: V
authors.lastname: Adhami
authors.affiliation: Department of Dermatology, University of Wisconsin, Madison, WI 53706, United States.
authors.forename: Hasan
authors.initials: H
authors.lastname: Mukhtar
authors.affiliation: Department of Cell and Regenerative Biology, University of Wisconsin, Madison, WI 53706, United States.
authors.forename: Suqing
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Radiology, University of Wisconsin, Madison, WI 53706, United States; Department of Medical Physics, University of Wisconsin, Madison, WI 53706, United States; Department of Biomedical Engineering, University of Wisconsin, Madison, WI 53706, United States; Department of Medicine, University of Wisconsin, Madison, WI 53706, United States; Department of Emergency Medicine, University of Wisconsin, Madison, WI 53706, United States.
authors.forename: Scott B
authors.initials: SB
authors.lastname: Reeder
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Wisconsin, Madison, WI 53706, United States.
authors.forename: Nader
authors.initials: N
authors.lastname: Sheibani
authors.affiliation: Department of Cell and Regenerative Biology, University of Wisconsin, Madison, WI 53706, United States; Molecular and Environmental Toxicology Center, University of Wisconsin, Madison, WI 53706, United States; Endocrinology and Reproductive Physiology Program, 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: D050154:Adiposity; D000367:Age Factors; D000818:Animals; D065633:Cytochrome P-450 CYP1B1 / Q000235:genetics / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism; D004041:Dietary Fats / Q000008:administration & dosage; D004734:Energy Metabolism; D005227:Fatty Acids / Q000378:metabolism*; D005234:Fatty Liver / Q000235:genetics / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D006706:Homeostasis; D020738:Leptin / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009765:Obesity / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress; D047493:PPAR alpha / Q000235:genetics / Q000378:metabolism; D013230:Stearoyl-CoA Desaturase / Q000235:genetics / Q000378:metabolism
chemical_list: D004041:Dietary Fats; D005227:Fatty Acids; D020738:Leptin; D047493:PPAR alpha; C585498:Cyp1b1 protein, mouse; D065633:Cytochrome P-450 CYP1B1; C490333:Scd1 protein, mouse; D013230:Stearoyl-CoA Desaturase
keywords: Cytochrome P450 1b1; Diet-induced obesity; Liver steatosis; PPARalpha; Sexual dimorphism