# A novel role of cholesterol and SR-BI in adipocyte biology > **NIH NIH R01** · UT SOUTHWESTERN MEDICAL CENTER · 2024 · $467,561 ## Abstract Project Summary (30 lines of text) Adipocytes play a key role in energy homeostasis, storing energy in the form of triglyceride (TG). In addition to neutral lipids, adipocytes contain abundant free cholesterol derived from circulating HDL cholesterol. There is a strong positive correlation between adipocyte cholesterol content and TG content, suggesting mechanistic linkage between adipocyte cholesterol and TG regulation. However, how adipocyte cholesterol is modulated by HDL cholesterol, and if and how cholesterol homeostasis in adipocytes influences TG accumulation are unknown. Scavenger receptor class B type I (SR-BI, encoded by SCARB1) is a high-affinity HDL receptor that is abundant in adipocytes. We recently discovered that mice selectively deficient in SR-BI in adipocytes (SR- BI∆AD) are protected from high fat diet-induced adiposity, their adipocytes are smaller, and they have decreased white adipose tissue (WAT) HDL cholesterol uptake and cellular cholesterol content. The overall goal of the project is to elucidate how HDL cholesterol and SR-BI influence adipocyte TG content, and to determine if adipocyte SR-BI expression is genetically regulated in humans to potentially impact the risk of obesity. Three Aims will be pursued in novel mouse models and cultured human adipocytes. Aim 1 will determine if HDL cholesterol and SR-BI promote adipocyte TG accumulation through transcriptional regulation of genes that control lipid homeostasis. We have determined that in SR-BI∆AD WAT the expression of liver X receptor β (LXRβ) and its target genes is downregulated and the content of oxysterols, which are LXR ligands, is decreased. Aim 1 will test the hypothesis that via HDL cholesterol uptake, adipocyte SR-BI promotes TG accumulation by providing the substrate for Cyp27a1 which converts cholesterol to oxysterols, leading to upregulation of LXRβ and its target genes. Aim 2 will determine if HDL cholesterol and SR-BI promote adipocyte TG accumulation by supporting adipocyte free fatty acid (FFA) uptake, which occurs in caveolae, which are cholesterol-rich plasma membrane domains. By electron microscopy we have discovered that caveolae content is markedly decreased in SR-BIAD adipocytes. Aim 2 will test the hypothesis that SR-BI-mediated HDL cholesterol uptake promotes FFA uptake and subsequent TG accumulation by supporting caveolae formation and maintenance. Aim 3 will determine how adipocyte SR-BI expression is transcriptionally regulated in humans, and if there is a genetic predisposition to obesity related to adipocyte SR-BI expression. Using a novel deep learning algorithm, we have identified a potential distal enhancer for SCARB1 within a region on Chr 12 harboring SNPs highly associated with obesity. In cultured human adipocytes, CRISPR/Cas9 deletion of the candidate region decreases SR-BI expression. Using further mutagenesis and interrogation of transcription factor binding sites, we will test the hypothesis that there is a remote enhancer of... ## Key facts - **NIH application ID:** 10918250 - **Project number:** 5R01DK130961-02 - **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER - **Principal Investigator:** Chieko Mineo - **Activity code:** R01 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2024 - **Award amount:** $467,561 - **Award type:** 5 - **Project period:** 2023-09-01 → 2027-08-31 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10918250 ## Citation > US National Institutes of Health, RePORTER application 10918250, A novel role of cholesterol and SR-BI in adipocyte biology (5R01DK130961-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10918250. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*