From:  PPARs in molecular pathogenesis and drug treatment of type 2 diabetes-related MASLD

 Linking isoform-specific PPAR biology to clinical manifestations and therapeutic outcomes in T2D-associated MASLD.

IsoformPredominant expressionKey biological role(s)Typical clinical consequence(s) when signalling is impairedRepresentative therapeutic outcome(s) when the isoform is pharmacologically activated
PPARαPredominant in liver, heart, and muscleInduces mitochondrial and peroxisomal β-oxidation and ketogenesis, enhancing hepatic FFA disposalAccumulation of intra-hepatic triglycerides and higher ALT/AST levels increase the risk of simple steatosis progressing to MASHFibrate monotherapy modestly lowers liver-fat content and transaminases but shows limited histological reversal of fibrosis in humans (cf. Table 1, e.g., fenofibrate, clofibrate)
PPARβ/δUbiquitous; muscle-centricPromotes fatty-acid uptake and oxidation in skeletal muscle and liver; supports mitochondrial biogenesis via PGC-1αReduced metabolic flexibility, peripheral insulin resistance and higher circulating FFAs that spill over to the liver contribute to this progressionEarly-phase β/δ agonists improve insulin sensitivity in pre-clinical MASLD, but long-term human data remain scarce; safety and durability are still under evaluation
PPARγAdipose-dominant; inducible in liverGoverns adipocyte differentiation and safe lipid storage; enhances systemic insulin sensitivityAdipocyte dysfunction triggers ectopic fat deposition, worsens insulin resistance and leads to an inflammatory adipokine profileThiazolidinediones (e.g., Pioglitazone) improve NAS and achieve MASH resolution in ~35–40% of biopsy-proven cases but cause weight gain and fluid retention (see Table 1)
Pan-PPARSimultaneous α + β/δ + γIntegrates oxidation (α, β/δ) with adipose buffering and insulin sensitisation (γ), while counter-modulating NF-κB-driven inflammationThe combined dysfunction of these factors fuels lipotoxicity, metaflammation and accelerates fibrosisLanifibranor 1.2 g/day resolves MASH without worsening fibrosis in ~49% and improves ≥ 1 stage of fibrosis in ~48% of patients, outperforming placebo in a 24-week RCT
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ALT: Alanine aminotransferase; AST: aspartate aminotransferase; FFA: free fatty acid; MASH: metabolic dysfunction-associated steatohepatitis; MASLD: metabolic dysfunction-associated steatotic liver disease; NAS: nonalcoholic fatty liver disease activity score; PPAR: peroxisome proliferator-activated receptor; RCT: randomized controlled trial; T2D: type 2 diabetes.