Heterozygous Midnolin Knockout Attenuates Severity of Nonalcoholic Fatty Liver Disease in Mice Fed a Western-Style Diet High in Fat, Cholesterol, and Fructose

Authors

Soo-Mi Kweon
Jose Irimia-Dominguez
Gayeoun Kim
Patrick T Fueger
Kinji Asahina
Keith K Lai
Daniela S Allende
Quincy R Lai
Chih-Hong Lou
Walter M Tsark
Ju Dong Yang
Dominic S Ng
Ju-Seog Lee
Patrick Tso
Wendong Huang
Keane K Y Lai

Publication Date

8-1-2023

Journal

American Journal of Physiology-Gastrointestinal and Liver Physiology

Abstract

Although midnolin has been studied for over 20 years, its biological roles in vivo remain largely unknown, especially due to the lack of a functional animal model. Indeed, given our recent discovery that the knockdown of midnolin suppresses liver cancer cell tumorigenicity and that this antitumorigenic effect is associated with modulation of lipid metabolism, we hypothesized that knockout of midnolin in vivo could potentially protect from nonalcoholic fatty liver disease (NAFLD) which has become the most common cause of chronic liver disease in the Western world. Accordingly, in the present study, we have developed and now report on the first functional global midnolin knockout mouse model. Although the overwhelming majority of global homozygous midnolin knockout mice demonstrated embryonic lethality, heterozygous knockout mice were observed to be similar to wild-type mice in their viability and were used to determine the effect of reduced midnolin expression on NAFLD. We found that global heterozygous midnolin knockout attenuated the severity of NAFLD in mice fed a Western-style diet, high in fat, cholesterol, and fructose, and this attenuation in disease was associated with significantly reduced levels of large lipid droplets, hepatic free cholesterol, and serum LDL, with significantly differential gene expression involved in cholesterol/lipid metabolism. Collectively, our results support a role for midnolin in regulating cholesterol/lipid metabolism in the liver. Thus, midnolin may represent a novel therapeutic target for NAFLD. Finally, our observation that midnolin was essential for survival underscores the broad importance of this gene beyond its role in liver biology.

Keywords

cholesterol, large droplet fat, midnolin (Midn), nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH)

Comments

Data Availability Statement

PMID: 37129245