Interplay Between Adiponectin, AMPK, and PPAR-α Signaling in Fatty Liver–Associated Cirrhosis: Linking Lipid Metabolism, Oxidative Stress, and Hepatic Fibrosis

Abstract

Cirrhosis resulting from fatty liver disease is a significant global health concern, marked by the development of metabolic disturbances, lipid deposition, oxidative damage and fibrosis. This progresses from steatosis to steatohepatitis and finally cirrhosis, with intricate metabolic and inflammatory crosstalk. Here, we discuss the interaction between adiponectin, AMP-activated protein kinase (AMPK), and peroxisome proliferator-activated receptor alpha (PPAR-α) pathways in modulating hepatic lipid metabolism, oxidative stress, and fibrogenesis. Adiponectin, an anti-inflammatory adipokine, has beneficial effects on hepatic metabolic balance through promotion of β-oxidation and suppression of lipogenesis. It exerts its actions largely via activation of AMPK and PPAR-α pathways through adiponectin receptors AdipoR1 and AdipoR2. AMPK is a key energy sensor that enhances lipid metabolism, enhances mitochondrial efficiency and alleviates oxidative stress, whereas PPAR-α is a transcriptional regulator of β-oxidation and lipid clearance pathways. The interconnected signaling between adiponectin, AMPK and PPAR-α represents a key regulatory network that prevents hepatic steatosis, reduces oxidative stress, and inhibits hepatic stellate cell activation leading to fibrosis. But in fatty liver disease, this signaling pathway is down-regulated causing defective lipid metabolism, augmented reactive oxygen species (ROS) generation and increased fibrogenesis. This interlinked signaling network offers insight into disease mechanisms and potential treatment strategies. Therapeutic approaches to modulate the adiponectin–AMPK-PPAR-α axis may provide innovative opportunities to re-establish metabolic homeostasis, limit oxidative damage, and halt the progression of fatty liver to cirrhosis