Aerobic capacity and exercise mediate protection against hepatic steatosis via enhanced bile acid metabolism

Authors: KUGLER, BENJAMIN - University Of Kansas; MAURER, ADRIANNA - University Of Kansas; FU, XIAORONG - University Of Texas Southwestern Medical Center; FRANCZAK, EDZIU - University Of Kansas; ERNST, NICK - University Of Kansas; SCHWARTZE, KEVIN - University Of Kansas; ALLEN, JULIE - University Of Kansas; LI, TAINGANG - University Of Oklahoma Health Sciences Center; CRAWFORD, PETER - University Of Minnesota; KOCH, LAUREN - University Of Toledo; BRITTON, STEVEN - University Of Michigan; Shankar, Kartik; BURGESS, SHAWN - University Of Texas Southwestern Medical Center; THYFAULT, JOHN - University Of Kansas

Submitted to: Function
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/1/2025
Publication Date: N/A
Citation: N/A

Interpretive Summary: Cardiorespiratory fitness is an important predictor of overall health outcomes including lower risk of liver diseases. This study looked at how fitness and exercise impact liver health, specifically how the liver handles bile acids (BAs), which help digest fats. The investigators studied rats that are bred to have either low or high cardiorespiratory fitness and found that naturally fit rats and mice that exercised made more bile acids in their livers. This suggests that being active helps the liver process fats better. To see if this was crucial, they removed a gene that makes bile acids in some mice. These mice, even with exercise, didn't improve their fatty livers. This means that making more bile acids through exercise is likely key to protecting the liver from fat buildup. The studies suggest important links between being fit or exercising and how it helps your liver by boosting bile acid production, which is important for keeping the liver healthy.

Technical Abstract: High cardiorespiratory fitness and exercise show evidence of altering bile acid (BA) metabolism and are known to protect or treat diet-induced hepatic steatosis, respectively. Here, we tested the hypothesis that high intrinsic aerobic capacity and exercise both increase hepatic BA synthesis measured by the incorporation of 2H2O. We also leveraged mice with inducible liver-specific deletion of Cyp7a1 (LCyp7a1KO), which encodes the rate-limiting enzyme for BA synthesis, to test if exercise-induced BA synthesis is critical for exercise to reduce hepatic steatosis. The synthesis of hepatic BA, cholesterol, and de novo lipogenesis was measured in rats bred for either high (HCR) vs. low (LCR) aerobic capacity consuming acute and chronic high-fat diets. HCR rats had increased synthesis of cholesterol and certain BA species in the liver compared to LCR rats. We also found that chronic exercise with voluntary wheel running (VWR) (4 weeks) increased newly synthesized BAs of specific species in male C57BL/6J mice compared to sedentary mice. Loss of Cyp7a1 resulted in fewer new BAs and increased liver triglycerides compared to controls after a 10-week high-fat diet. Additionally, exercise via VWR for 4 weeks effectively reduced hepatic triglycerides in the high-fat diet-fed control male and female mice as expected; however, exercise in LCyp7a1KO mice did not lower liver triglycerides in either sex. These results show that aerobic capacity and exercise increase hepatic BA metabolism, which may be critical for combating hepatic steatosis.