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Sex- and age-associated factors drive the pathophysiology of MASLD.
- Source :
-
Hepatology communications [Hepatol Commun] 2024 Aug 26; Vol. 8 (9). Date of Electronic Publication: 2024 Aug 26 (Print Publication: 2024). - Publication Year :
- 2024
-
Abstract
- Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) is strongly associated with obesity. Sex and age affect MASLD prevalence and pathophysiology. The use of animal models fed Western-style diets is vital for investigating the molecular mechanisms contributing to metabolic dysregulation and for facilitating novel drug target identification. However, the sex-associated and age-associated mechanisms underlying the pathophysiology remain poorly understood. This knowledge gap limits the development of personalized sex-specific and age-specific drug treatments.<br />Methods: Young (7 wk) and aged (52 wk) male and female mice were fed a high-fat diet (HFD) or low-fat diet. Liver metabolome (>600 molecules) and transcriptome profiles were analyzed.<br />Results: Male and female mice fed an HFD developed obesity, glucose intolerance, and hepatic steatosis. However, fasting blood glucose, insulin, and serum alanine aminotransferase levels were higher in males fed an HFD, indicating a more severe metabolic disease. In addition, males showed significant increases in liver diacylglycerides and glycosylceramides (known mediators of insulin resistance and fibrosis), and more changes in the transcriptome: extracellular matrix organization and proinflammatory genes were elevated only in males. In contrast, no major increase in damaging lipid classes was observed in females fed an HFD. However, aging affected the liver to a greater extent in females. Acylcarnitine levels were significantly reduced, suggestive of changes in fatty acid oxidation, and broad changes in the transcriptome were observed, including reduced oxidative stress response gene expression and alterations in lipid partitioning genes.<br />Conclusions: Here, we show distinct responses to an HFD between males and females. Our study underscores the need for using both sexes in drug target identification studies, and characterizing the molecular mechanisms contributing to the MASLD pathophysiology in aging animals.<br /> (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)
- Subjects :
- Animals
Female
Male
Mice
Sex Factors
Age Factors
Disease Models, Animal
Liver metabolism
Liver physiopathology
Transcriptome
Fatty Liver metabolism
Fatty Liver physiopathology
Mice, Inbred C57BL
Non-alcoholic Fatty Liver Disease metabolism
Non-alcoholic Fatty Liver Disease physiopathology
Non-alcoholic Fatty Liver Disease etiology
Insulin Resistance
Metabolome
Glucose Intolerance physiopathology
Glucose Intolerance metabolism
Diet, High-Fat adverse effects
Obesity metabolism
Obesity physiopathology
Subjects
Details
- Language :
- English
- ISSN :
- 2471-254X
- Volume :
- 8
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- Hepatology communications
- Publication Type :
- Academic Journal
- Accession number :
- 39185904
- Full Text :
- https://doi.org/10.1097/HC9.0000000000000523