Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, CA, USA; The Paul F. Glenn Center for Aging Research, University of California, Berkeley, Berkeley, CA, USA; Cardiovascular Research Institute, UCSF, San Francisco, CA, USA.
Department of Nutritional Sciences and Toxicology, University of California at Berkeley, Berkeley, CA, USA.
J Lipid Res. 2021;62:100051. doi: 10.1016/j.jlr.2021.100051. Epub 2021 Feb 23.
Oxysterols are oxidized derivatives of cholesterol that play regulatory roles in lipid biosynthesis and homeostasis. How oxysterol signaling coordinates different lipid classes such as sterols and triglycerides remains incompletely understood. Here, we show that 4β-hydroxycholesterol (HC) (4β-HC), a liver and serum abundant oxysterol of poorly defined functions, is a potent and selective inducer of the master lipogenic transcription factor, SREBP1c, but not the related steroidogenic transcription factor SREBP2. By correlating tracing of lipid synthesis with lipogenic gene expression profiling, we found that 4β-HC acts as a putative agonist for the liver X receptor (LXR), a sterol sensor and transcriptional regulator previously linked to SREBP1c activation. Unique among the oxysterol agonists of the LXR, 4β-HC induced expression of the lipogenic program downstream of SREBP1c and triggered de novo lipogenesis both in primary hepatocytes and in the mouse liver. In addition, 4β-HC acted in parallel to insulin-PI3K-dependent signaling to stimulate triglyceride synthesis and lipid-droplet accumulation. Thus, 4β-HC is an endogenous regulator of de novo lipogenesis through the LXR-SREBP1c axis.
氧化固醇是胆固醇的氧化衍生物，在脂质生物合成和动态平衡中发挥调节作用。氧化固醇信号如何协调不同的脂质类，如固醇和甘油三酯，仍不完全清楚。在这里，我们表明 4β-羟基胆固醇（HC）（4β-HC），一种肝脏和血清中丰富的功能尚未明确的氧化固醇，是主脂质生成转录因子 SREBP1c 的有效和选择性诱导剂，但不是相关的甾体生成转录因子 SREBP2。通过将脂质合成的追踪与脂肪生成基因表达谱相关联，我们发现 4β-HC 作为肝 X 受体（LXR）的一种假定激动剂起作用，LXR 是一种固醇传感器和转录调节剂，先前与 SREBP1c 的激活有关。在 LXR 的氧化固醇激动剂中，4β-HC 是独特的，它诱导 SREBP1c 下游的脂肪生成程序的表达，并在原代肝细胞和小鼠肝脏中触发从头脂肪生成。此外，4β-HC 与胰岛素-PI3K 依赖性信号平行作用，刺激甘油三酯合成和脂滴积累。因此，4β-HC 通过 LXR-SREBP1c 轴是从头脂肪生成的内源性调节剂。
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