HSD17B6 delays type 2 diabetes development via inhibiting SREBP activation

Fengxiang Wei; Yan Gu; Lizhi He; Anil Kapoor; Xiaozeng Lin; Ying Dong; Yingying Su; Sandra Vega Neira; Damu Tang

doi:10.1016/j.metabol.2023.155631

HSD17B6 delays type 2 diabetes development via inhibiting SREBP activation

Metabolism. 2023 Aug:145:155631. doi: 10.1016/j.metabol.2023.155631. Epub 2023 Jun 16.

Authors

Fengxiang Wei¹, Yan Gu², Lizhi He², Anil Kapoor², Xiaozeng Lin², Ying Dong², Yingying Su², Sandra Vega Neira², Damu Tang³

Affiliations

¹ The Genetics Laboratory, Longgang District Maternity and Child Healthcare Hospital of Shenzhen City, Longgang District, Shenzhen, Guangdong, China; Urological Cancer Center for Research and Innovation (UCCRI), St Joseph's Hospital, Hamilton, ON L8N 4A6, Canada; The Research Institute of St Joe's Hamilton, St Joseph's Hospital, Hamilton, ON L8N 4A6, Canada; Department of Surgery, McMaster University, Hamilton, ON L8S 4K1, Canada. Electronic address: haowei727499@163.com.
² Urological Cancer Center for Research and Innovation (UCCRI), St Joseph's Hospital, Hamilton, ON L8N 4A6, Canada; The Research Institute of St Joe's Hamilton, St Joseph's Hospital, Hamilton, ON L8N 4A6, Canada; Department of Surgery, McMaster University, Hamilton, ON L8S 4K1, Canada.
³ Urological Cancer Center for Research and Innovation (UCCRI), St Joseph's Hospital, Hamilton, ON L8N 4A6, Canada; The Research Institute of St Joe's Hamilton, St Joseph's Hospital, Hamilton, ON L8N 4A6, Canada; Department of Surgery, McMaster University, Hamilton, ON L8S 4K1, Canada. Electronic address: damut@mcmaster.ca.

PMID: 37330135
DOI: 10.1016/j.metabol.2023.155631

Abstract

Background: The SREBP/SCAP/INSIG complex plays an essential role in SREBP activation and de novo lipogenesis. Whether the activation process is affected by hydroxysteroid 17-beta dehydrogenase 6 (HSD17B6) remains unknown.

Methods: SREBP's transcriptional activities were analyzed using an SRE-luciferase (SRE-luc) reporter in 293T cells, Huh7 hepatoma cells, and primary human hepatocytes following a variety of conditions, including ectopic expression of HSD17B6, HSD17B6 mutants defective in its enzymatic activities, knockdown of HSD17B6, and cholesterol starvation. The interaction between HSD17B6 and SREBP/SCAP/INSIG complex was analyzed in 293T cells, Huh7 cells and mouse liver upon ectopic expression of HSD17B6 and its mutants; the interaction was also analyzed using endogenous proteins. The impacts of HSD17B6 on SREBP target expression, glucose tolerance, diet-induced obesity, and type 2 diabetes (T2D) were examined using Huh7 cells in vitro, and with C57BL/6 and NONcNZO10/LtJ T2D mice in vivo.

Results: HSD17B6 binds to the SREBP/SCAP/INSIG complex and inhibits SREBP signaling in cultured hepatocytes and mouse liver. Although HSD17B6 plays a role in maintaining the equilibrium of 5α-dihydrotestosterone (DHT) in the prostate, a mutant defective in androgen metabolism was as effective as HSD17B6 in inhibiting SREBP signaling. Hepatic expression of both HSD17B6 and the defective mutant improved glucose intolerance and reduced hepatic triglyceride content in diet-induced obese C57BL/6 mice, while hepatic knockdown of HSD17B6 exacerbated glucose intolerance. Consistent with these results, liver-specific expression of HSD17B6 in a polygenic NONcNZO10/LtJ T2D mice reduced T2D development.

Conclusions: Our study unveils a novel role of HSD17B6 in inhibiting SREBP maturation via binding to the SREBP/SCAP/INSIG complex; this activity is independent of HSD17B6's sterol oxidase activity. Through this action, HSD17B6 improves glucose tolerance and attenuates the development of obesity-induced T2D. These findings position HSD17B6 as a potential therapeutic target for T2D therapy.

Keywords: HSD17B6 (SDR9C6); Lipid metabolism; Obesity; SREBP; Type 2 diabetes.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Diabetes Mellitus, Type 2* / genetics
Glucose
Glucose Intolerance*
Humans
Intracellular Signaling Peptides and Proteins
Male
Mice
Mice, Inbred C57BL
Obesity
Racemases and Epimerases
Sterol Regulatory Element Binding Protein 1 / metabolism

Substances

Sterol Regulatory Element Binding Protein 1
Intracellular Signaling Peptides and Proteins
Glucose
HSD17B6 protein, human
Racemases and Epimerases