Selective Pharmacological Activation of PPARα/δ/γ Alters the Triglyceride Composition of Fatty Liver in a...

Various high-fat diets have been used to create animal models of metabolic dysfunction-associated steatotic liver disease (MASLD) and to evaluate the effect of various therapeutic drugs. We determined the effects of PPARα/δ/γ subtype-selective agonists (pemafibrate, seladelpar, and pioglitazone, respectively) on the hepatic triglyceride (TG) profile using LC-MS in a MASLD mouse model established by administering a high-fat/high-cholesterol/high-cholic acid (HFCC) diet combined with cyclodextrin-containing water, which is thought to induce fatty liver over a short period. The livers of mice fed the HFCC/CDX diet for four weeks exhibited an approximately fivefold increase in the summed TG LC-MS signal per unit liver weight and altered TG composition compared with normal livers of mice administered a standard diet/water. Specifically, the proportion of TG54 (TG with 54 carbon atoms) species doubled, whereas the proportion of TG52 decreased by 38%. Pemafibrate did not alter the relative total TG signal but decreased the proportion of some TG58/TG56 species and increased the proportion of some TG56/TG52 species. Seladelpar did not alter the relative total TG signal, while only slightly altering TG composition. Pioglitazone reduced the relative total TG signal by 44%, which included a decrease in the proportion of polyunsaturated fatty acid-rich TG54 and an increase in the proportion of TG58/TG56 with 1-3 unsaturated bonds. We are the first to demonstrate that selective activation of PPARα/δ/γ has different effects on the TG profile in fatty liver.