HSD17B6 通过抑制 SREBP 激活来延缓 2 型糖尿病的发展。

HSD17B6 delays type 2 diabetes development via inhibiting SREBP activation.

机构信息

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.

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.

出版信息

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

DOI:10.1016/j.metabol.2023.155631

PMID:37330135

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.

摘要

背景

固醇调节元件结合蛋白（SREBP）/SREBP 裂解激活蛋白（SCAP）/胰岛素诱导基因表达蛋白（INSIG）复合物在 SREBP 激活和从头合成脂质中起着至关重要的作用。但其激活过程是否受到羟甾醇 17-β 脱氢酶 6（HSD17B6）的影响尚不清楚。

方法

通过在 293T 细胞、Huh7 肝癌细胞和原代人肝细胞中使用 SRE 荧光素酶（SRE-luc）报告基因，分析各种条件下（包括异位表达 HSD17B6、缺乏其酶活性的 HSD17B6 突变体、HSD17B6 敲低和胆固醇饥饿）SREBP 的转录活性。在异位表达 HSD17B6 及其突变体后，在 293T 细胞、Huh7 细胞和小鼠肝脏中分析 HSD17B6 与 SREBP/SCAP/INSIG 复合物之间的相互作用；还使用内源性蛋白进行了分析。通过体外 Huh7 细胞和体内 C57BL/6 和 NONcNZO10/LtJ 2 型糖尿病（T2D）小鼠，研究了 HSD17B6 对 SREBP 靶基因表达、葡萄糖耐量、饮食诱导肥胖和 T2D 的影响。

结果

HSD17B6 与 SREBP/SCAP/INSIG 复合物结合，并抑制培养的肝细胞和小鼠肝脏中的 SREBP 信号。尽管 HSD17B6 在维持前列腺中 5α-二氢睾酮（DHT）的平衡中起作用，但缺乏雄激素代谢功能的突变体在抑制 SREBP 信号方面与 HSD17B6 一样有效。肝表达 HSD17B6 和缺陷突变体均可改善饮食诱导肥胖的 C57BL/6 小鼠的葡萄糖耐量并降低肝甘油三酯含量，而肝 HSD17B6 敲低则加剧葡萄糖不耐受。与这些结果一致，在多基因 NONcNZO10/LtJ T2D 小鼠中，肝特异性表达 HSD17B6 可减少 T2D 的发生。

结论

我们的研究揭示了 HSD17B6 通过与 SREBP/SCAP/INSIG 复合物结合抑制 SREBP 成熟的新作用；这种活性独立于 HSD17B6 的固醇氧化酶活性。通过这种作用，HSD17B6 改善了葡萄糖耐量并减轻了肥胖诱导的 T2D 的发展。这些发现将 HSD17B6 定位为 T2D 治疗的潜在治疗靶标。