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

Abstract

Oxysterols are oxidized derivatives of cholesterol that play signaling roles in lipid biosynthesis and homeostasis. Here we show that 4β-hydroxycholesterol (4β-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, 4β-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, 4β-HC induced expression of the lipogenic program downstream of SREBP1c, and triggered de novo lipogenesis both in primary hepatocytes and in mouse liver. 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.

Ablation of fatty acid desaturase 2 (FADS2) exacerbates hepatic triacylglycerol and cholesterol accumulation in polyunsaturated fatty acid‐depleted mice

“…For example, side-chain oxysterols such as 27-hydroxycholesterol (27-OH) and 25-hydroxycholesterol (25-OH) inhibit the activation of SREBP-1 [27]. On the other hand, it has been recently reported that 4b-hydroxycholesterol (4b-OH) promotes SREBP-1c transcript and de novo lipogenesis [28]. The hepatic level of 27-OH and 4b-OH was increased in the KO-DEF group, whereas the difference of 25-OH level was not observed among three groups (Fig.…”

Thermal proteome profiling reveals distinct target selectivity for differentially oxidized oxysterols

“…[31] Very recently 4β-HC has been shown to act as a pro-lipogenic factor by enhancing Sterol Regulatory Element Binding Protein 1c (SREBP1c) expression in an LXR-dependent manner. [32] In this context, we found that 4β-HC (de)stabilized a series of transcriptional regulators, including the general transcription factor 3C (GTF3C) and two components of the super elongation complex, cyclin-dependent kinase 9 (CDK9) and AF4/FMR2 family member 4 (AFF4). This raises the possibility that transcriptional elongation of SREBP1c may require 4β-HC's ability to interact with the SEC.…”