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, clinicaltrials.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 non-alcoholic 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.

Figure 1.. Proposed role of HSD17B13 in modulating disease progression in NAFLD.

HSD17B13 expression is induced by liver x receptor-α (LXR-α) through sterol regulatory binding protein-1c (SREBP-1c) in the hepatocyte nucleus. HSD17B13 is then targeted from the endoplasmic reticulum to lipid droplets. Wild type HSD17B13 catalyzes the conversion of retinol to retinaldehyde. Genetic polymorphism in HSD17B13 results in a loss of this enzymatic activity, which increases retinol-retinol binding protein (RBP4)-transthyretin (TTR) transport from hepatocytes. PNPLA3 is located on lipid droplets, and it has hydrolase activity towards retinyl esters in hepatic stellate cells (HSCs). The I148M mutation results in a loss of retinyl esterase activity with retinol retention in HSCs. Retinoids play an important role in hepatic immunomodulation and suppression of HSC-mediated fibrogenesis. Abbreviations: CRBP1, cellular retinol-binding protein 1.

Figure 2.. Worldwide prevalence of HSD17B13 rs72613567 minor allele in general population.

Data based on MAF in the general population are as follows: Africa, America, East Asia, Europe, South Asia: 1000 Genomes project. Abbreviations: MAF, minor allele frequency.

Figure 3.. Worldwide prevalence of HSD17B13 rs72613567 minor allele in patients with NAFLD.

Data based on MAF in patients with NAFLD are as follows: Argentina, data from Pirola; Austria, calculated from genotype frequency; China, data from Sun; Finland, calculated from genotype frequency; Germany, calculated from genotype frequency; Italy, data from Anstee; Malaysia, data from Ting; South Korea, data from Koo; Switzerland, calculated from genotype frequency; US, data from Serper. Abbreviations: MAF, minor allele frequency.

Figure 4.. siRNA-based inhibition of HSD17B13 expression.

The small interfering RNA (siRNA) targeting HSD17B13 mRNA is conjugated with a triantennary N-Acetylgalactosamine (GalNAc). GalNAc binds to the asialoglycoprotein receptor (ASGPR), which is highly expressed on hepatocytes, thus targeting siRNA to the liver. The siRNA-ASGPR complex is then taken into hepatocytes by clathrin-mediated endocytosis, where the siRNA causes HSD17B13 mRNA destruction through the RNA-induced silencing complex (RISC) in the cytoplasm.