LAUSR

Low aerobic capacity (i.e., capacity to utilize oxygen in metabolic pathways) has proven to be a risk factor for hepatic steatosis. We have previously reported that increased hepatic mitochondrial function caused by exercise and high aerobic capacity is associated with higher fecal bile acid loss. In addition, other labs have shown that bile acid sequestrants (BA-seq) that block bile acid absorption in the gut and drives-up fecal bile acid loss is associated with an upregulation of hepatic mitochondrial function. So far, the connection between bile acid metabolism and mitochondrial function is unknown. Here we utilized rats artificially selected to be higher-capacity runners (HCR) and low-capacity runners (LCR) with distinct intrinsic aerobic capacities and hepatic mitochondrial function. We hypothesized that aerobic capacity would induce distinct differences in fecal bile acid loss and mitochondrial function when on a BA-seq. Male and female HCRs and LCRs (8 months of age) were randomly assigned to either a low-fat diet (LFD, 10% fat), high-fat diet (HFD, 45% fat), or HFD with cholestyramine (i.e., BA-Seq) for 24 weeks. Animals were euthanized, and feces and livers were collected. Fresh mitochondria were then isolated from the liver, and mitochondrial respiration and H2O2 emission was analyzed (O2k high-resolution respirometry). Statistical analysis was performed by a three-way ANOVA within sex with an alpha set at 0.05. BA-Seq increased fecal energy loss and BA content more than control diets (P<0.05 main effect of BA-Seq). However, HCRs with a BA-seq have greater fecal BA content than their LCR counterpart on a BA-Seq (P<0.05). Interestingly, male and female HCR livers displayed elevated hepatic mitochondrial respiration rates (State 2, State 3, FCCP) and mitochondrial coupling efficiency (State 2/State 3) and a reduction in free radical production (H2O2:O2) utilizing a fatty acid fuel source compared to LCRs (P<0.05, main effect of strain). However, diet and BA seq did not alter mitochondrial function in either strain. Overall, we provide evidence that elevated intrinsic aerobic capacity promotes greater sensitivity to BA-seq. However, enhanced fecal energy and BA loss do not alter hepatic mitochondrial function regardless of intrinsic aerobic capacity. R01DK121497 This is the full abstract presented at the American Physiology Summit 2023 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.