KLF15 Enables Rapid Switching between Lipogenesis and Gluconeogenesis during Fasting.
KLF15 Enables Rapid Switching between Lipogenesis and Gluconeogenesis during Fasting.
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DOI：
10.1016/j.celrep.2016.07.069
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发表时间：
2016-08-30
期刊：
影响因子：
8.8
通讯作者：
Shimano H
中科院分区：
文献类型：
--
作者：
Takeuchi Y;Yahagi N;Aita Y;Murayama Y;Sawada Y;Piao X;Toya N;Oya Y;Shikama A;Takarada A;Masuda Y;Nishi M;Kubota M;Izumida Y;Yamamoto T;Sekiya M;Matsuzaka T;Nakagawa Y;Urayama O;Kawakami Y;Iizuka Y;Gotoda T;Itaka K;Kataoka K;Nagai R;Kadowaki T;Yamada N;Lu Y;Jain MK;Shimano H
肝脏脂肪生成受营养调节，即，在禁食期间下调，在餐后状态期间上调，作为对营养环境的适应。虽然已知转录因子SREBP-1c的表达水平的改变对于营养调节的脂肪生成至关重要，但控制Srebf 1基因表达的上游机制仍不清楚。在这里，我们表明，禁食诱导的转录因子KLF 15，一个关键的调节器，形成一个复杂的LXR/RXR，特别是在Srebf 1启动子。该复合物募集辅阻遏物RIP 140而不是辅激活物SRC 1，导致在低血糖和PKA激活之前的禁食早期和血糖正常期间Srebf 1和下游脂肪生成酶表达减少。通过这种机制，KLF 15过表达特异性改善高胆固醇血症，而不影响LXR介导的胆固醇代谢。这些发现揭示了葡萄糖和脂质代谢之间的关键分子联系，对治疗高脂血症具有治疗意义。Takeuchi等人发现KLF 15通过与LXR/RXR/RIP 140复合物相互作用抑制SREBP-1c转录。通过这种机制，KLF 15通过将脂肪生成转换为脂肪生成来促进禁食适应。KLF 15过表达可改善高脂血症而不影响LXR介导的胆固醇代谢
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 SREBP-1c are known to be critical for nutritionally-regulated lipogenesis, upstream mechanisms governing Srebf1 gene 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 with therapeutic implications for the treatment of hyperlipidemia. Takeuchi et al. find that KLF15 suppresses SREBP-1c transcription through interaction with the LXR/RXR/RIP140 complex. Through this mechanism, KLF15 promotes a fasting adaptation by switching lipogenesis to gluconeogenesis. KLF15 overexpression ameliorates hypertriglyceridemia without affecting LXR-mediated cholesterol metabolism.
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DOI：
10.1073/pnas.95.11.5987
发表时间：
1998-05-26
影响因子：
11.1
作者：
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通讯作者：
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影响因子：
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发表时间：
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影响因子：
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作者：
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影响因子：
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作者：
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影响因子：
7.7
作者：
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