KSRP is critical in governing hepatic lipid metabolism through controlling Per2 expression
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 hepati...
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| Format: | Article |
| Language: | English |
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Elsevier
2015-02-01
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| Series: | Journal of Lipid Research |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0022227520356091 |
| _version_ | 1818690908217933824 |
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| author | Chu-Fang Chou Xiaolin Zhu Yi-Yu Lin Karen L. Gamble W. Timothy Garvey Ching-Yi Chen |
| author_facet | Chu-Fang Chou Xiaolin Zhu Yi-Yu Lin Karen L. Gamble W. Timothy Garvey Ching-Yi Chen |
| author_sort | Chu-Fang Chou |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-17T12:33:28Z |
| format | Article |
| id | doaj.art-e39036e8f1eb4779ba818d5a36d5ee5f |
| institution | Directory Open Access Journal |
| issn | 0022-2275 |
| language | English |
| last_indexed | 2024-12-17T12:33:28Z |
| publishDate | 2015-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Lipid Research |
| spelling | doaj.art-e39036e8f1eb4779ba818d5a36d5ee5f2022-12-21T21:48:27ZengElsevierJournal of Lipid Research0022-22752015-02-01562227240KSRP is critical in governing hepatic lipid metabolism through controlling Per2 expressionChu-Fang Chou0Xiaolin Zhu1Yi-Yu Lin2Karen L. Gamble3W. Timothy Garvey4Ching-Yi Chen5Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, AL 35294Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, AL 35294Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, AL 35294Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL 35294Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, AL 35294To whom correspondence should be addressed; Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, AL 35294; To whom correspondence should be addressedHepatic 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.http://www.sciencedirect.com/science/article/pii/S0022227520356091circadian rhythmsfatty acid synthesisKH-type splicing regulatory proteinlivernuclear receptors/sterol-regulatory element binding protein 1• period 2ribonucleic acid turnover |
| spellingShingle | Chu-Fang Chou Xiaolin Zhu Yi-Yu Lin Karen L. Gamble W. Timothy Garvey Ching-Yi Chen KSRP is critical in governing hepatic lipid metabolism through controlling Per2 expression Journal of Lipid Research circadian rhythms fatty acid synthesis KH-type splicing regulatory protein liver nuclear receptors/sterol-regulatory element binding protein 1• period 2 ribonucleic acid turnover |
| title | KSRP is critical in governing hepatic lipid metabolism through controlling Per2 expression |
| title_full | KSRP is critical in governing hepatic lipid metabolism through controlling Per2 expression |
| title_fullStr | KSRP is critical in governing hepatic lipid metabolism through controlling Per2 expression |
| title_full_unstemmed | KSRP is critical in governing hepatic lipid metabolism through controlling Per2 expression |
| title_short | KSRP is critical in governing hepatic lipid metabolism through controlling Per2 expression |
| title_sort | ksrp is critical in governing hepatic lipid metabolism through controlling per2 expression |
| topic | circadian rhythms fatty acid synthesis KH-type splicing regulatory protein liver nuclear receptors/sterol-regulatory element binding protein 1• period 2 ribonucleic acid turnover |
| url | http://www.sciencedirect.com/science/article/pii/S0022227520356091 |
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