2. Academic Validation
  3. Heterozygous midnolin knockout attenuates severity of nonalcoholic fatty liver disease in mice fed a Western-style diet high in fat, cholesterol, and fructose

Heterozygous midnolin knockout attenuates severity of nonalcoholic fatty liver disease in mice fed a Western-style diet high in fat, cholesterol, and fructose

  • Am J Physiol Gastrointest Liver Physiol. 2023 Aug 1;325(2):G147-G157. doi: 10.1152/ajpgi.00011.2023.
Soo-Mi Kweon 1,  Jose Irimia-Dominguez 2,  Gayeoun Kim 1,  Patrick T Fueger 2 3,  Kinji Asahina 4,  Keith K Lai 5 6,  Daniela S Allende 5,  Quincy R Lai 1,  Chih-Hong Lou 7,  Walter M Tsark 8,  Ju Dong Yang 9 10 11,  Dominic S Ng 12,  Ju-Seog Lee 13,  Patrick Tso 14,  Wendong Huang 15 3,  Keane K Y Lai 1 3
Affiliations

Affiliations

  • 1 Department of Cancer Biology and Molecular Medicine, Beckman Research Institute of City of Hope, Duarte, California, United States.
  • 2 Department of Molecular and Cellular Endocrinology and Comprehensive Metabolic Phenotyping Core, Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute of City of Hope, Duarte, California, United States.
  • 3 City of Hope Comprehensive Cancer Center, Duarte, California, United States.
  • 4 Central Research Laboratory, Shiga University of Medical Science, Seta Tsukinowa-cho, Otsu, Japan.
  • 5 Department of Pathology, Cleveland Clinic, Cleveland, Ohio, United States.
  • 6 Contra Costa Pathology Associates, Pleasant Hill, California, United States.
  • 7 Gene Editing and Viral Vector Core, Beckman Research Institute of City of Hope, Duarte, California, United States.
  • 8 Transgenic/Knockout Mouse Program, Center for Comparative Medicine, Beckman Research Institute of City of Hope, Duarte, California, United States.
  • 9 Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, California, United States.
  • 10 Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, California, United States.
  • 11 Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California, United States.
  • 12 Departments of Medicine, Physiology, and Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
  • 13 Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States.
  • 14 Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio, United States.
  • 15 Department of Diabetes Complications and Metabolism, Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute of City of Hope, Duarte, California, United States.
PMID: 37129245 DOI: 10.1152/ajpgi.00011.2023
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.NEW & NOTEWORTHY We have developed and now report on the first functional global midnolin knockout mouse model. We found that global heterozygous midnolin knockout attenuated the severity of nonalcoholic fatty liver disease (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.

Keywords

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

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