期刊
CELL REPORTS
卷 16, 期 9, 页码 2373-2386出版社
CELL PRESS
DOI: 10.1016/j.celrep.2016.07.069
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资金
- MEXT/JSPS KAKENHI [23116006, 15H03092, 21591123, 18590979, 26560392, 16K13040, 03J10558]
- Uehara Memorial Foundation
- ONO Medical Research Foundation
- Takeda Science Foundation
- Suzuken Memorial Foundation
- Japan Heart Foundation
- Kanae Foundation for the Promotion of Medical Science
- Senri Life Science Foundation
- Japan Foundation for Applied Enzymology
- Okinaka Memorial Institute for Medical Research
- NIH [HL119195l]
- Grants-in-Aid for Scientific Research [26560392, 26461357, 03J10558, 21591123, 16K13040, 15H04824, 15H03092, 18590979] Funding Source: KAKEN
Hepatic lipogenesis is nutritionally regulated (i.e., downregulated during fasting and upregulated during the postprandial state) as an adaptation to the nutritional environment. While alterations in the expression level of the transcription factor SREBP1c are known to be critical for nutritionally regulated lipogenesis, upstream mechanisms governing Srebf1 expression remain unclear. Here, we show that the fasting-induced transcription factor KLF15, a key regulator of gluconeogenesis, forms a complex with LXR/RXR, specifically on the Srebf1 promoter. This complex recruits the corepressor RIP140 instead of the coactivator SRC1, resulting in reduced Srebf1 and thus downstream lipogenic enzyme expression during the early and euglycemic period of fasting prior to hypoglycemia and PKA activation. Through this mechanism, KLF15 overexpression specifically ameliorates hypertriglyceridemia without affecting LXR-mediated cholesterol metabolism. These findings reveal a key molecular link between glucose and lipid metabolism and have therapeutic implications for the treatment of hyperlipidemia.
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