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.
Highlights
All cells must achieve and maintain a balanced composition of their internal membranes to grow, proliferate, or adapt to sudden changes in external conditions and nutrient availability [1]
The master steroidogenic transcription factor SREBP2, SREBP1c resides at the endoplasmic reticulum (ER) membrane, to which it is anchored via a single transmembrane helix
When cholesterol concentration in the ER membrane is low, SREBP1c and SREBP2 are transported to the Golgi apparatus via interaction with SREBP cleavageactivating protein, a cholesterol-sensing chaperone that favors their loading into COPII vesicles
Summary
To identify oxysterol ligands that could promote SREBP1c expression, we treated liver carcinoma–derived Huh cells with a panel of oxysterols selected among the most abundant in the bloodstream, including 4β-, 7β-, 19-, 20-, 24(S)-, 25-, and 27-HC. Of the unprocessed cytoplasmic form of both proteins but without transcriptional upregulation (Fig. 1B) These data suggest that, unlike other oxysterols that function as inhibitors of both SREBP1c and SREBP2, 4β-HC is a specific inducer of SREBP1c expression and activation. We hypothesized that 4β-HC may transcriptionally activate SREBP1c and its downstream lipogenic programs via the LXR Consistent with this possibility, cotreating cells with 4β-HC together with an LXR antagonist (GSK-2033) abolished 4β-HC–dependent induction of SREBP1c gene expression (Fig. 3A). To lipogenic gene induction, both GW3965 and 4β-HC had a modest but statistically significant 1.5-fold increase in C13-labeled C16:C16:C16 TAG, or trending toward significance for C16:C18:C16 TAG, whereas 24-HC caused no significant change (Fig. 3E) Combined, these data suggest that the prolipogenic action of 4β-HC is comparable, in mechanism and potency, to known LXR agonists. In keeping with the ability of 4β-HC to upregulate fatty acid biosynthetic genes via SREBP1c, treating Huh cells with 4β-HC (but not with its unnatural enantiomer, ent-4HC) for 72 h resulted in marked accumulation of lipid droplets (LDs), as revealed by staining with the lipophilic dye BODIPY 493/503
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