Enchen Zhou, Netherlands

Leiden University Medical Center Endocrinology

Presenter of 1 Presentation

Δ24-Dehydrocholesterol reductase (DHCR24): a novel target for the treatment of NASH

Session Type
Track 2 - Metabolism of Lipids and Lipoproteins
Date
06.10.2020, Tuesday
Session Time
10:00 - 11:13
Lecture Time
10:30 - 10:40

Abstract

Background and Aims

24-Dehydrocholesterol reductase (DHCR24) is the terminal enzyme in cholesterol biosynthesis converting the ultimate intermediate desmosterol into cholesterol. Desmosterol is an endogenous liver X receptor ligand with anti-inflammatory properties and reduces cholesterol and fatty acid biosynthesis. We aimed to investigate the therapeutic effects of DHCR24 inhibition by using the novel selective DHCR24 inhibitor SH42 on hepatic steatosis and inflammation, the two most important hallmarks of nonalcoholic steatohepatitis (NASH).

Methods

Male APOE*3-Leiden.CETP mice, a well-established translational model for lipoprotein metabolism that develops diet-induced human-like NASH characteristics, were fed a high fat and high cholesterol diet with or without simultaneous SH42 treatment (3x0.5mg/week, i.p.). After 8 weeks, liver steatosis and inflammation were assessed. Lipidomics and lipid mediator analyses were carried out on plasma and liver.

Results

DHCR24 inhibition via SH42 markedly increased plasma desmosterol levels (+5,600%), without influencing food intake and body weight. SH42 decreased plasma cholesteryl ester (-24%) and fatty acids (-19%) levels whilst not affecting diacylglycerol(DAG) and triacylglycerol(TAG) levels. Notably, SH42 largely increased plasma 19,20-epoxydocosapentaenoic acid levels (+210%), a well described and potent anti-inflammatory/pro-resolving lipid mediator. In the liver, SH42 reduced DAG (-21%), TAG (-38%) and cholesteryl esters (-26%). Strikingly, liver histological assessment showed that SH42 abolished diet-induced hepatic steatosis, inflammation, ballooning and crown-like structure formation.

Conclusions

Inhibition of DHCR24 by SH42 abolishes hepatic steatosis, inflammation and damage as induced by a diet containing high fat and high cholesterol. DHCR24 inhibition is a potential novel therapeutic strategy for the treatment of NASH by killing two birds with one stone, i.e. hepatic steatosis and inflammation.

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