The SREBP Dependent Regulation of HIF-1α Links Insulin Driven Glucose and Lipid Metabolism

Abstract

Dysregulation of lipid and glucose metabolism contributes to the development and progression of chronic conditions such as obesity, type 2 diabetes, and cancer. Sterol Regulatory Element-Binding Proteins (SREBPs) are central to lipid and cholesterol biosynthesis, while Hypoxia-Inducible Factor 1-alpha (HIF-1α) regulates adaptive responses to hypoxia. Although both transcription factors can be regulated by insulin, their potential crosstalk under insulin stimulation has not been clearly defined. This study investigates the role of the SREBP pathway in regulating insulin-induced HIF-1α expression and activity in both cancerous and non-cancerous models. We found that insulin increases HIF-1α protein levels in HepG2 cells without affecting its mRNA expression, indicating post-transcriptional regulation. Knockdown of SREBP2 significantly reduced HIF-1α protein levels and its transcriptional activity. Interestingly, 25-hydroxycholesterol suppressed HIF-1α in HepG2 but elevated it in MCF7 cells, suggesting cell-type-specific differences. In primary adipose-derived stem cells, insulin increased both HIF-1α mRNA and protein, but this response was attenuated by SREBP2 knockdown. Expression of VEGF, a HIF-1α target gene, was also reduced in SREBP2-deficient ADSCs. Overall, our findings suggest that SREBP2 plays an important role in supporting insulin-mediated HIF-1α expression and function, offering new insights into the interplay between lipid and glucose metabolism with potential implications in metabolic disorders and cancer

Date of Award	2025
Original language	American English
Awarding Institution	HBKU College of Health & Life Sciences