Exercise increases myocardial free fatty acid oxidation in subjects with metabolic dysfunction-associated fatty liver disease

Abstract

Background and aims: Metabolic dysfunction-associated fatty liver disease (MAFLD) is associated with dyslipidemia and may promote cardiac lipotoxicity. Myocardial free fatty acids (FFA) oxidation (MO_FFA) is normal in pre-diabetes, but reduced in heart failure. We hypothesized that during exercise MO_FFA, very low-density lipoprotein triglycerides (VLDL-TG) secretion, hepatic FFA utilization, and lactate production differ among obese subjects with and without MAFLD.

Methods: Nine obese subjects with MAFLD and 8 matched subjects without MAFLD (Control) without a history of heart failure and cardiovascular disease were compared before and after 90-min exercise at 50% Peak oxygen consumption. Basal and exercise induced cardiac and hepatic FFA oxidation, uptake and re-esterification and VLDL-TG secretion were measured using [¹¹C]palmitate positron-emission tomography and [1-¹⁴C]VLDL-TG.

Results: In the heart, increased MO_FFA was observed after exercise in MAFLD, whereas MO_FFA decreased in Control (basal vs exercise, MAFLD: 4.1 (0.8) vs 4.8 (0.8) μmol·100 ml^-1 min^-1; Control: 4.9 (1.8) vs 4.0 (1.1); μmol·100 ml^-1 min^-1, mean (SD), p < 0.048). Hepatic FFA fluxes were significantly lower in MAFLD than Control and increased ≈ two-fold in both groups. VLDL-TG secretion was 50% greater in MAFLD at rest and similarly suppressed during exercise. Plasma lactate increased significantly less in MAFLD than Control during exercise.

Conclusions: Using robust tracer-techniques we found that obese subjects with MAFLD do not downregulate MO_FFA during exercise compared to Control, possibly due to diminished lactate supply. Hepatic FFA fluxes are significantly lower in MAFLD than Control, but increase similarly with exercise. VLDL-TG export remains greater in MAFLD compared to Control. Basal and post-exercise myocardial and hepatic FFA, VLDL-TG and lactate metabolism is abnormal in subjects with MAFLD compared to Control.

Keywords: Exercise; FFA; Fatty liver disease; Free fatty acids; Lipoprotein metabolism; MAFLD; PET palmitate Tracer; PET scanning; VLDL-TG tracer; VLDL-Triglycerides.