HSD17B13: A Potential Therapeutic Target for NAFLD

Abstract

Nonalcoholic fatty liver disease (NAFLD), especially in its inflammatory form (steatohepatitis, NASH), is closely related to the pathogenesis of chronic liver disease. Despite substantial advances in the management of NAFLD/NASH in recent years, there are currently no efficacious therapies for its treatment. The biogenesis and expansion of lipid droplets (LDs) are critical pathophysiological processes in the development of NAFLD/NASH. In the past decade, increasing evidence has demonstrated that lipid droplet-associated proteins may represent potential therapeutic targets for the treatment of NAFLD/NASH given the critical role they play in regulating the biogenesis and metabolism of lipid droplets. Recently, HSD17B13, a newly identified liver-enriched, hepatocyte-specific, lipid droplet-associated protein, has been reported to be strongly associated with the development and progression of NAFLD/NASH in both mice and humans. Notably, human genetic studies have repeatedly reported a robust association of HSD17B13 single nucleotide polymorphisms (SNPs) with the occurrence and severity of NAFLD/NASH and other chronic liver diseases (CLDs). Here we briefly overview the discovery, tissue distribution, and subcellular localization of HSD17B13 and highlight its important role in promoting the pathogenesis of NAFLD/NASH in both experimental animal models and patients. We also discuss the potential of HSD17B13 as a promising target for the development of novel therapeutic agents for NAFLD/NASH.

Targeted therapeutics and novel signaling pathways in non-alcohol-associated fatty liver/steatohepatitis (NAFL/NASH)

“…davurica) MCD diet-fed db/db mouse model ↓Lipid accumulation ↓Inflammation ↑Antioxidative proteins 444 Suppresses activation of HSCs Emodin HSC-T6 cell model ↓Proliferation and activation of HSCs ↓TGFβ1/Smad signaling pathway in activated HSCs 454 , 455 Overexpression of human HNF4α (hepatocyte nuclear factor 4α) AAV8-ALB-hHNF4α High-fat/cholesterol/fructose (HFCF) diet-fed mouse model ↓Steatohepatitis ↓TG ↑FAO ↑VLDL secretion 632 TAZ inhibitor GalNAc-siTAZ NASH diet-fed mouse model ↓Hepatic inflammation ↓Liver injury ↓Fibrosis 567 Notch inhibitor GSI NASH diet-fed mouse model ↓HSC activation and liver fibrosis ↑Goblet cell metaplasia 568 Ncst ASO NASH diet-fed mouse model ↓Fibrosis (expression of HSC markers and collagen deposition) No effect on serum transaminases and liver inflammation 568 Antioxidative stress agents Antioxidative stress agents Matrine HFD or MCD diet-fed mouse model ↓Hepatic inflammation ↓Lipid peroxides ↓ALT and AST ↓Fibrosis 633 , 634 Polaprezinc MCD diet-fed mouse model ↓Fibrosis ↓Lipid peroxidation ↓Inflammation No effect on the development of steatosis. 635 Genetic approaches HSD17B13 inhibitor INI-678 Human cell “3D liver-on-a-chip” model ( https://inipharm.com/ ) ↓Markers of liver fibrosis ( α-SMA, Col-I ) 562 PNPLA3-rs738409 (I148M) variant inhibitor Minor allele-specific small interfering RNA (siRNA) ...…”

“…ARO-HSD, a ribonucleic acid interference (RNAi) therapy, significantly reduced the mRNA and protein levels of hepatic HSD17B13 , leading to a decrease in serum ALT in the phase 1 trial (NCT04202354). 558 , 562 …”

Metabolic-associated fatty liver disease from childhood to adulthood: State of art and future directions

“…In addition, robust evidence showed that the downregulation of the MBOAT7 gene predisposed to fatty liver development both in children and adults[ 34 , 52 , 53 ]. In contrast, the HSD17B13 variant has been recognized as a protective factor against liver injury and its progression[ 38 , 54 , 55 ]. As described for other well-known single nucleotide polymorphisms related to fatty liver, this variant has been found also to influence kidney function[ 56 ].…”

“…Conversely, no significant differences for the main clinical and biochemical variables between NAFLD and MAFLD were found in a large cohort of 780 adult patients with biopsy-proven fatty liver diagnosis [ 55 ]. Taking into account the alcohol consumption in MAFLD definition, patients with MAFLD with significant alcohol intake showed a worse hepatic profile (characterized by higher steatosis degree and transaminase levels) compared to those with MAFLD only[ 55 ].…”

What’s new in non-alcoholic fatty liver disease?

“…This discovery has led to the development of ARO-HSD, an RNA-interfering therapeutic that selectively targets HSD17B13 mRNA in hepatocytes with early signals that the intervention reduces HSD17B13 expression in phase 1 and 2a clinical trials (NCT04565717; NCT04202354). 33…”