Combining three approved drugs targeting PPAR subtypes in a 4-week diet-induced early-stage fatty liver disease mouse model

The combination of seladelpar and pioglitazone may serve as a promising therapeutic option for early-stage metabolic dysfunction-associated steatotic liver disease (MASLD).

• Approved/safe PPARα/δ/γ-selective agonists were evaluated in a mouse model of early-stage MASLD.
• Specific symptoms of MASLD, including hepatic steatosis, inflammation, and limited fibrosis, developed within 4 weeks of a high-fat/high-cholesterol/high-cholic acid diet.
• Pioglitazone alone and the combination of pemafibrate and seladelpar improved fibrosis but did not affect triglyceride accumulation or inflammation.
• Treatment with pemafibrate or pioglitazone, alone or in combination, reduced the expression levels of inflammatory and fibrotic marker genes in the liver.
• MALDI mass spectrometry imaging indicated that certain triglyceride species accumulated in the liver of MASLD mice and were reduced by pioglitazone or the combination treatment.

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