Selective Pharmacological Activation of PPARα/δ/γ Alters the Triglyceride Composition of Fatty Liver in a Diet-Induced MASLD Mouse Model

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.