4β-Hydroxycholesterol is a prolipogenic factor that promotes SREBP1c expression and activity through the liver X receptor

Ofer Moldavski; Peter-James H Zushin; Charles A Berdan; Robert J Van Eijkeren; Xuntian Jiang; Mingxing Qian; Daniel S Ory; Douglas F Covey; Daniel K Nomura; Andreas Stahl; Ethan J Weiss; Roberto Zoncu

doi:10.1016/j.jlr.2021.100051

4β-Hydroxycholesterol is a prolipogenic factor that promotes SREBP1c expression and activity through the liver X receptor

J Lipid Res. 2021:62:100051. doi: 10.1016/j.jlr.2021.100051. Epub 2021 Feb 23.

Authors

Affiliations

¹ 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.
² Department of Nutritional Sciences and Toxicology, University of California at Berkeley, Berkeley, CA, USA.
³ 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.
⁴ Diabetic Cardiovascular Disease Center, Washington University School of Medicine, St Louis, MO, USA.
⁵ Department of Developmental Biology, Washington University School of Medicine, St Louis, MO, USA.
⁶ Cardiovascular Research Institute, UCSF, San Francisco, CA, USA.
⁷ 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. Electronic address: rzoncu@berkeley.edu.

Abstract

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.

Keywords: SREBP1c; de-novo-lipogenesis; insulin; lipid droplets; liver-X-Receptor; oxysterol.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Animals
Gene Expression Regulation / drug effects
Hepatocytes / metabolism
Humans
Hydroxycholesterols* / metabolism
Hydroxycholesterols* / pharmacology
Lipogenesis*
Liver / metabolism
Liver X Receptors* / agonists
Liver X Receptors* / genetics
Liver X Receptors* / metabolism
Male
Mice
Mice, Inbred C57BL
Orphan Nuclear Receptors / agonists
Orphan Nuclear Receptors / metabolism
Signal Transduction
Sterol Regulatory Element Binding Protein 1* / genetics
Sterol Regulatory Element Binding Protein 1* / metabolism

Substances

Liver X Receptors
Hydroxycholesterols
Sterol Regulatory Element Binding Protein 1
cholest-5-ene-3,4-diol
Srebf1 protein, mouse
Orphan Nuclear Receptors

Abstract

Publication types

MeSH terms

Substances

Grants and funding