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bioRxiv · 10.1101/2020.08.20.256487

4 β-hydroxycholesterol is a pro-lipogenic factor that promotes SREBP1c expression and activity through Liver X-receptor.

Moldavski, O.·Zushin, P.-J. H.·Berdan, C. A.·van Eijkeren, R. J.·Jiang, X.·Qian, M.·Ory, D. S.·Covey, D. F.·Nomura, D.·Stahl, A.·Weiss, E.·Zoncu, R.
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Abstract

Oxysterols are oxidized derivatives of cholesterol that play signaling roles in lipid biosynthesis and homeostasis. Here we show that 4{beta}-hydroxycholesterol (4{beta}-HC), a liver and serum abundant oxysterol of poorly defined function, is a potent and selective inducer of the master lipogenic transcription factor, Sterol Regulatory Element Binding Protein 1c (SREBP1c), but not the related steroidogenic transcription factor SREBP2. Mechanistically, 4{beta}-HC acts as a putative agonist for Liver X receptor (LXR), a sterol sensor and transcriptional regulator previously linked to SREBP1c activation. Unique among the oxysterol agonists of LXR, 4{beta}-HC induced expression of the lipogenic program downstream of SREBP1c, and triggered de novo lipogenesis both in primary hepatocytes and in mouse liver. 4{beta}-HC-acted in parallel to insulin-PI3K-dependent signaling to stimulate triglyceride synthesis and lipid droplet accumulation. Thus, 4{beta}-HC is an endogenous regulator of de novo lipogenesis through the LXR-SREBP1c axis.

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Moldavski, O., Zushin, P.-J. H., Berdan, C. A., van Eijkeren, R. J., Jiang, X., Qian, M., Ory, D. S., Covey, D. F., Nomura, D., Stahl, A., Weiss, E., Zoncu, R.. 2020-08-21. 4 β-hydroxycholesterol is a pro-lipogenic factor that promotes SREBP1c expression and activity through Liver X-receptor.. https://doi.org/10.1101/2020.08.20.256487

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