Emerging insights into PPARα′s role in lean metabolic dysfunction-associated steatotic liver disease: Implications for targeted therapies

Abstract

Lean metabolic dysfunction-associated steatotic liver disease (MASLD), defined as hepatic steatosis in individuals with normal BMI (<25 kg/m² in non-Asians; <23 kg/m² in Asians), is a clinically paradoxical phenotype in which patients face risks of progressive fibrosis, cardiovascular events, and liver-related mortality comparable to or exceeding obese counterparts. Visceral adiposity, dietary stressors, cholesterol overload, and genetic susceptibility involving PNPLA3 variants and PPARA polymorphisms synergistically disrupt hepatic lipid homeostasis. At the core of this dysregulation lies peroxisome proliferator-activated receptor alpha (PPARα), a master transcriptional regulator of hepatic fatty acid oxidation, ketogenesis, and anti-inflammatory signaling. PPARα suppression aries through convergent mechanisms, including aging-related RAGE signaling, fructose-mediated epigenetic silencing, gut‒liver axis disruption, and lipotoxicity, operating independently of systemic obesity. This review demonstrates that: (1) impaired PPARα activity underlies lean MASLD pathogenesis through transcriptional, epigenetic, and post-translational suppression; (2) synthetic PPARα agonists show limited applicability in this metabolically fragile population; and (3) natural product-derived modulators engage PPARα alongside FXR and LXR networks to restore metabolic balance. The PPARα–FGF21–ketogenesis axis and nuclear receptor crosstalk provide the mechanistic rationale for network-level therapeutic approaches. We advocate for spatially selective hepatic PPARα reactivation guided by lean-specific biomarker and genotype-stratified trial design.