Hepatic HSD17B6 is dispensable for diet-induced fatty liver disease in mice

Metabolic dysfunction-associated fatty liver disease (MAFLD) affects up to a third of the global population, which causes huge both clinical and economic burdens. However, its therapeutic strategy is still limited. Steroid dysregulation plays a pivotal role in the homeostasis of lipid metabolism. 17-beta-hydroxysteroid dehydrogenase type 6 (HSD17B6)—one member of 17β-HSDs, encoded by the gene Hsd17b6, catalyzes the synthesis of androsterone and estrone—steroid hormones. However, whether the manipulation of HSD17B6 could ameliorate diet-induced fatty liver disease remains unknown. Here, we found that the expression of Hsd17b6 is enriched in the liver in both humans and mice. The data of single-cell RNA-seq suggests that Hsd17b6 appears to be exclusively expressed in hepatocytes—the parenchymal cells of the liver. Furthermore, the hepatic expression of Hsd17b6 is correlated with fatty liver disease. A mouse model with Hsd17b6 deletion in the liver (HLKO) is successfully generated via the administration of AAV8 expressing Cre recombinase (driven by TBG—a liver-specific promoter) and sgRNAs of Hsd17b6 to Cre-dependent Cas9 mice. Control and HLKO mice were challenged with the high-fat choline-deficient diet—a diet widely used for the model generation of fatty liver disease. Interestingly, the HLKO liver shows a special proteome signature, with the altered proteins enriched in the Golgi apparatus. However, the deletion of Hsd17b6 does not affect fatty liver disease in terms of fat accumulation, inflammation, and hepatic fibrosis. Taken together, our study suggests that the expression of Hsd17b6 is enriched in the liver and correlated with fatty liver disease but its hepatic deletion does not affect diet-induced fatty liver disease. •Hsd17b6 is exclusively expressed in hepatocytes—the parenchymal cells of the liver.•The hepatic expression of Hsd17b6 is associated with fatty liver disease.•Hepatic Hsd17b6 is dispensable for diet-induced fatty liver disease.