title: KSRP is critical in governing hepatic lipid metabolism through controlling Per2 expression.
abstract: Hepatic lipid metabolism is controlled by integrated metabolic pathways. Excess accumulation of hepatic TG is a hallmark of nonalcoholic fatty liver disease, which is associated with obesity and insulin resistance. Here, we show that KH-type splicing regulatory protein (KSRP) ablation reduces hepatic TG levels and diet-induced hepatosteatosis. Expression of period 2 (Per2) is increased during the dark period, and circadian oscillations of several core clock genes are altered with a delayed phase in Ksrp(-/-) livers. Diurnal expression of some lipid metabolism genes is also disturbed with reduced expression of genes involved in de novo lipogenesis. Using primary hepatocytes, we demonstrate that KSRP promotes decay of Per2 mRNA through an RNA-protein interaction and show that increased Per2 expression is responsible for the phase delay in cycling of several clock genes in the absence of KSRP. Similar to Ksrp(-/-) livers, both expression of lipogenic genes and intracellular TG levels are also reduced in Ksrp(-/-) hepatocytes due to increased Per2 expression. Using heterologous mRNA reporters, we show that the AU-rich element-containing 3' untranslated region of Per2 is responsible for KSRP-dependent mRNA decay. These findings implicate that KSRP is an important regulator of circadian expression of lipid metabolism genes in the liver likely through controlling Per2 mRNA stability.
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, AL 35294.
authors.forename: Chu-Fang
authors.initials: CF
authors.lastname: Chou
authors.affiliation: Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, AL 35294.
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, AL 35294.
authors.forename: Yi-Yu
authors.initials: YY
authors.lastname: Lin
authors.affiliation: Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL 35294.
authors.forename: Karen L
authors.initials: KL
authors.lastname: Gamble
authors.affiliation: Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, AL 35294.
authors.forename: W Timothy
authors.initials: WT
authors.lastname: Garvey
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, AL 35294.
authors.forename: Ching-Yi
authors.initials: CY
authors.lastname: Chen
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004435:Eating / Q000235:genetics / Q000502:physiology; D005786:Gene Expression Regulation / Q000235:genetics*; D022781:Hepatocytes / Q000378:metabolism; D047468:Immunoprecipitation; D050356:Lipid Metabolism / Q000235:genetics*; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D056950:Period Circadian Proteins / Q000235:genetics* / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D012261:Ribonucleoproteins / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*
chemical_list: C507913:Khsrp protein, mouse; C513312:Per2 protein, mouse; D056950:Period Circadian Proteins; D016601:RNA-Binding Proteins; D012261:Ribonucleoproteins; D015534:Trans-Activators
keywords: KH-type splicing regulatory protein; circadian rhythms; fatty acid synthesis; liver; nuclear receptors/sterol-regulatory element binding protein 1• period 2; ribonucleic acid turnover; steatosis; triglyceride