Emerging insights into PPARα's role in lean metabolic dysfunction-associated steatotic liver disease: Implications for targeted therapies.
- 1Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, National Quality Control Center for Donated Organ Procurement, Hubei Key Laboratory of Medical Technology on Transplantation, Hubei Provincial Clinical Research Center for Natural Polymer Biological Liver, Wuhan 430071, China.
- 2Department of pharmacy, Maternal and Child Health Hospital of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430070, China.
- 3Department of Pharmacology, Taikang Medical School (School of Basic Medical Sciences), Wuhan University, Wuhan 430071, China.
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.
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BibTeX
@article{yang2026emerging,
title = {{Emerging insights into PPARα's role in lean metabolic dysfunction-associated steatotic liver disease: Implications for targeted therapies.}},
author = {Yafei Yang and Furong Zhang and Zhuang Peng and Yafei Wu and Ling Li and Zixia Shen and Qifa Ye and Jiang Yue and Shufang Na},
journal = {Acta pharmaceutica Sinica. B},
year = {2026},
month = jun,
doi = {10.1016/j.apsb.2026.06.029},
url = {https://europepmc.org/article/MED/42948748},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Emerging insights into PPARα's role in lean metabolic dysfunction-associated steatotic liver disease: Implications for targeted therapies.
AU - Yafei Yang
AU - Furong Zhang
AU - Zhuang Peng
AU - Yafei Wu
AU - Ling Li
AU - Zixia Shen
AU - Qifa Ye
AU - Jiang Yue
AU - Shufang Na
PY - 2026
DA - 2026/06/18
JO - Acta pharmaceutica Sinica. B
DO - 10.1016/j.apsb.2026.06.029
UR - https://europepmc.org/article/MED/42948748
AB - 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.
SN - 2211-3835
SN - 2211-3843
ER -