HSD17B13 Liquid-liquid Phase Separation Promotes Leukocyte Adhesion in Chronic Liver Inflammation

Overview

Journal J Mol Cell Biol

Publisher Oxford University Press

Specialty Molecular Biology

Date 2024 May 1

PMID 38692847

Authors

Jing Ye

Xiyu Huang

Manman Yuan

Jinglin Wang

Ru Jia

Tianyi Wang

Yang Tan

Shun Zhu

Qiang Xu

Xingxin Wu

Affiliations

Soon will be listed here.

Abstract

The rs72613567:TA polymorphism in 17-beta hydroxysteroid dehydrogenase 13 (HSD17B13) has been found to reduce the progression from steatosis to metabolic dysfunction-associated steatohepatitis (MASH). In this study, we sought to define the pathogenic role of HSD17B13 in triggering liver inflammation. Here, we demonstrate that HSD17B13 forms liquid-liquid phase separation (LLPS) around lipid droplets in the livers of MASH patients. The dimerization of HSD17B13 supports the LLPS formation and promotes its enzymatic function. HSD17B13 LLPS increases the biosynthesis of platelet activating factor (PAF), which in turn promotes fibrinogen synthesis and leukocyte adhesion. Blockade of the PAF receptor or STAT3 pathway inhibits the fibrinogen synthesis and leukocyte adhesion. Importantly, adeno-associated viral-mediated xeno-expression of human HSD17B13 exacerbates western diet/carbon tetrachloride-induced liver inflammation in Hsd17b13-/- mice. In conclusion, our results suggest that HSD17B13 LLPS triggers liver inflammation by promoting PAF-mediated leukocyte adhesion, and targeting HSD17B13 phase transition could be a promising therapeutic approach for treating hepatic inflammation in chronic liver disease.

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