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Abstract The leading cause of death among patients with metabolic dysfunction‐associated steatotic liver disease (MASLD) is cardiovascular disease. A significant percentage of MASLD patients develop heart failure driven by functional and structural alterations in the heart. Previously, we observed cardiac dysfunction in hepatocyte‐specific peroxisome proliferator‐activated receptor alpha knockout (PparaHepKO), a mouse model that exhibits hepatic steatosis independent of obesity and insulin resistance. The goal of the present study was to determine mechanisms that underlie hepatic steatosis‐induced cardiac dysfunction in PparaHepKO mice. Experiments were performed in 30‐week‐old PparaHepKO and littermate control mice fed regular chow. We observed decreased cardiomyocyte contractility (0.17 ± 0.02 vs. 0.24 ± 0.02 μm, p

IntroductionDegenerin proteins, such as βENaC and ASIC2, have been implicated in cardiovascular function. However, their role in metabolic syndrome have not been studied. To begin to assess this interaction, we evaluated the impact of a high fat diet (HFD) on mice lacking normal levels of ASIC2 (ASIC2-/-) and βENaC (βENaCm/m).MethodsTwenty-week-old male and female mice were placed on a 60% HFD for 12 weeks. Body weight was measured weekly, and body composition by non-invasive ECHO MRI and fasting blood glucose were measured at 0, 4, 8 and 12 weeks. A glucose tolerance test was administered after 12 weeks. Differences between ASIC2-/-/βENaCm/m and WT groups were compared using independent t-tests or ANOVA where appropriate within each sex. Data are presented as mean ± SEM and ASIC2-/-/βENaCm/m vs. WT. ResultsAt 20 weeks of age, ASIC2-/-/βENaCm/m mice (n=9F/10M) weighed less and gained less weight than WT (n=12F/16M). Total body fat and lean body masses were reduced in female and male ASIC2-/-/βENaCm/m mice. Total body fat and lean body masses as % control were identical at the end of 12 weeks. Fasting blood glucoses were lower in female and male ASIC2-/-/βENaCm/m vs. WT mice after 12 weeks HFD. The area under the curve for the glucose tolerance test was reduced in female and tended (p=.079) to decrease in male ASIC2-/-/βENaCm/m. Plasma leptin and insulin were reduced in female and male ASIC2-/-/βENaCm/m vs. WT mice. Plasma insulin in female ASIC2-/-/βENaCm/m mice remained unchanged throughout the HFD period. Liver and liver fat masses, as well as percent liver fat, were reduced in both female and male ASIC2-/-/βENaCm/m mice after HFD. Plasma triglycerides, cholesterol, LDL- and HDL-cholesterols were markedly improved in male and/or female ASIC2-/-/βENaCm/m following the HFD.DiscussionThese novel findings suggest that loss of ASIC2 and βENaC offer a significant protection against HFD-induced metabolic syndrome.

Over the past 55 years, the heme oxygenase (HO) system has emerged as a pivotal player in a myriad of cellular, tissue, and integrative physiological processes [...]