Review article: the role of HSD17B13 on global epidemiology, natural history, pathogenesis and treatment of NAFLD

Abstract

Background: Non-alcoholic fatty liver disease (NAFLD) occurs in around a quarter of the global population and is one of the leading causes of chronic liver disease. The phenotypic manifestation and the severity of NAFLD are influenced by an interplay of environmental and genetic factors. Recently, several inactivating variants in the novel 17-Beta hydroxysteroid dehydrogenase 13 (HSD17B13) gene have been found to be associated with a reduced risk of chronic liver diseases, including NAFLD. Aims:To review the existing literature on the epidemiology of HSD17B13 and discuss its role in the natural history, disease pathogenesis and treatment of NAFLD. Methods:We extensively searched relevant literature in PubMed, Google Scholar, clini caltr ials.gov and the reference list of articles included in the review.Results: HSD17B13 is a liver-specific, lipid droplet (LD)-associated protein that has enzymatic pathways involving steroids, pro-inflammatory lipid mediators and retinol.The estimated prevalence of the best characterised HSD17B13 variant (rs72613567) ranges from 5% in Africa to 34% in East Asia. Loss-of-function variants in HSD17B13 are protective against the progression of NAFLD from simple steatosis to nonalcoholic steatohepatitis (NASH), liver fibrosis, cirrhosis and hepatocellular carcinoma. Emerging data from mechanistic and preclinical studies with RNA interference (RNAi) and small molecule agents indicate that inhibiting HSD17B13 activity may prevent NAFLD progression. Conclusions:The loss-of-function polymorphisms of the newly identified HSD17B13 gene mitigate the progression of NAFLD. It is important to understand the exact mechanism by which these variants exert a protective effect and implement the gathered knowledge in the treatment of NAFLD.

Discovery of a Novel Potent and Selective HSD17B13 Inhibitor, BI-3231, a Well-Characterized Chemical Probe Available for Open Science

“…The unrelenting rise in the worldwide prevalence of obesity, metabolic syndrome and Type 2 diabetes , engenders an increasing burden of associated complications and co-morbidities including cardiovascular disease, nephropathy, neuropathy, retinopathies and nonalcoholic fatty liver disease (NAFLD). , The increased incidence of NAFLD that may progress to nonalcoholic steatohepatitis (NASH) and cirrhosis represents a looming critical burden on clinical and economic resources . Presenting initially as a silent accumulation of neutral lipids in the liver, disease progression is characterized by development of severe hepatic inflammation and advancing fibrosis, with an elevated risk of hepatocellular carcinoma (HCC) and ultimate loss of liver function (end-stage liver disease, ESLD) .…”

Editorial: Unveiling new horizons for liver steatosis genetic variants beyond hepatocellular carcinoma diagnosis ‐ exploring the potential of HSD17B13 inhibition

“…4 Genetic variation in HSD17B13 does not protect against hepatic fat accumulation, but modulates the risk of steatohepatitis, cirrhosis and evolution to HCC. [5][6][7] The mechanism is related to the loss-offunction of enzymatic activity. However, the substrates mediating the phenotypic expression of liver damage in individuals with wild-type HSD17B13, possibly including retinoids, steroid hormones, eicosanoids, other lipid species with pro-inflammatory/lipotoxic activity or a more complex alteration of metabolism, are still undefined.…”

“…However, the substrates mediating the phenotypic expression of liver damage in individuals with wild-type HSD17B13, possibly including retinoids, steroid hormones, eicosanoids, other lipid species with pro-inflammatory/lipotoxic activity or a more complex alteration of metabolism, are still undefined. [5][6][7][8] Since hepatic silencing or inhibition of HSD17B13 is well tolerated and decreases liver enzymes in experimental models of steatohepatitis and early stage clinical trials in individuals with SLD, 9 the authors suggested the exciting hypothesis that HSD17B13 inhibition represents a new promising avenue for treatment of HCC. 4 The possible mechanisms linking HSD17B13 status with HCC are depicted in…”

A coding variant in the microsomal triglyceride transfer protein reduces both hepatic steatosis and plasma lipids

“…[4][5][6] Previous studies revealed an increased risk of NAFLD of first-degree relatives of patients with NAFLD. 6,7 The susceptibility, development and progression of NAFLD are highly influenced by genetic factors, for example, PNPLA3 rs738409 or HSD17B13 rs72613567, 8 and therefore, understanding genetic associations with NAFLD is critical for investigating the underlying molecular mechanisms of the disease.…”