17β-hydroxysteroid dehydrogenases in the progression of nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease (NAFLD) is a liver disease characterized by steatosis and excessive lipid deposition in hepatic cells. NAFLD is a spectrum of liver disease ranging from nonalcoholic fatty liver to nonalcoholic steatohepatitis (NASH), characterized by steatosis, inflammation, and hepatocyte injury with or without fibrosis (Friedman, Neuschwander-Tetri, Rinella, & Sanyal, 2018). NAFLD is estimated to affect approximately 20/10,000 people annually (Lee et al., 2019). The overall prevalence of NAFLD is higher in men. However, in the advanced fibrosis stage of NASH, the prevalence of NAFLD appears to increase in postmenopausal women, suggesting a protective role of estradiol (E2) in liver disease (Lazo et al., 2015; Lee, Lee, et al., 2019). Although NAFLD is receiving worldwide attention, the performance of drug research and development in this area is unsatisfactory (Abdelmalek, 2021; Targher, Byrne, & Tilg, 2020). Basic research related to NAFLD has made great progress, focusing on pathogenesis (Francque et al., 2021; Kazankov et al., 2019; Loomba, Friedman, & Shulman, 2021). However, the development of the disease and the role of environmental and genetic factors in NAFLD remain to be further elucidated.

Recently, 17β-hydroxysteroid dehydrogenase type 13 (HSD17B13) has been associated with the clinical outcome of liver disease, and some advances have been made (Abul-Husn et al., 2018; Ma et al., 2019; Thomas, 2018). The expression of HSD17B13, a new LD-associated protein, is enhanced in NAFLD patients. The high expression of HSD17B13 in the hepatocytes facilitated the progression of NAFLD by directly stabilizing the intracellular lipid drops and indirectly activating hepatic stellate cells (Wang et al., 2022). A recent study of human liver lipidome and transcriptome revealed that a loss-of-function variant in HSD17B13 increases hepatic phospholipids, especially phosphatidylcholines and phosphatidylethanolamines, and decreases fibrosis (Luukkonen et al., 2020). Multiple treatments and drug development targeting HSD17B13 have achieved great prospects in clinical practices. As a member of the 17β-hydroxysteroid dehydrogenase superfamily (HSD17Bs), HSD17B13 is mainly responsible for intrahepatic lipid metabolism and has shown great potential as a therapeutic target (Luukkonen et al., 2023; Wang et al., 2022). HSD17Bs have been identified in fifteen mammalian subtypes that exhibit similar biological activity to HSD17B13 (Saloniemi, Jokela, Strauss, Pakarinen, & Poutanen, 2012). In this review, we summarize the profile and physiological function of HSD17Bs, and highlight the development strategies of anti-NAFLD drugs targeting HSD17Bs, to provide a reference for the basic and applied research on HSD17Bs.

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