Background: The prevalence of non alcoholic fatty liver disease (NAFLD) is ~30% higher in the obese population. However, among patients living with NAFLD, 40% are not obese and half of them are lean. Although being mostly studied in obese individuals, the progression of NAFLD in lean patients may involve cardiac manifestations as well. Our hypothesis states that lean NAFLD patients also develop cardiac complications, independently of pre-existent metabolic disruptions, mechanisms of which remain to be fully understood, especially when considering the sexual dimorphism of the disease. Method: To address the underlying mechanisms of the progression of NAFLD independently of obesity, we used a murine model of hepatic mitochondrial deficiency, achieved through a hepato-specific knockout (KO) of Lrpprc. KO mice thus develop microvesicular steatosis without obesity in both sexes which was extensively characterized at the molecular and metabolic level in liver, plasma and heart. Our results unveiled a sex-dependent hepatic and cardiac phenotypic remodeling. KO male mice, to a greater extent than females, showed sustained fasting hypoglycemia and increased insulin sensitivity. Males also showed a more inflammatory hepatic profile characterized by a significant increase of F4/80 staining in immunohistological analyses (3-fold). Furthermore, only males exhibited an increase in the circulating hepatokine FGF21 (1.74-fold) and an increase in VLDLs lipoproteins while HDLs lipoproteins were decreased. In contrast, KO females showed a modest and global decrease of the lipoprotein profile. As such, sex differences occurred also in the heart since only males showed diastolic dysfunction while females’ cardiac function remained unaffected despite mitochondrial defects such as impairments in mitochondrial biogenesis, dynamics and oxidative capacities. Noteworthy, we also observed a significant and inverse correlation between glycemia and an index for cardiac relaxation only in males. Conclusion: Overall, this study underscores the value of this model for NAFLD without obesity where sex-dependent damage in the liver, the plasma and the heart are highlighted. Canadian Institutes of Health Research (CIHR), Montreal Heart Institute Foundation, Heart and Stroke Foundation of Canada, Cardiometabolic Health, Diabetes and Obesity Research Network. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
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