Sicheng Zhang, Lucydalila Cedillo, Claudio J Villanueva
The adipose-liver axis is central to controlling systemic energy homeostasis, with free fatty acids (FFAs) acting as critical metabolic signals that coordinate lipid metabolism between these organs. Under physiological conditions like fasting, FFAs released via adipocyte lipolysis are taken up by the liver to support β-oxidation for ketogenesis, triglyceride synthesis, and lipoprotein production. However, in obesity and insulin resistance, chronic elevation of lipolysis exceeds hepatic lipid-handling capacity, contributing to metabolic dysfunction-associated steatotic liver disease (MASLD), lipotoxicity, and inflammation. To manage fluctuating lipid loads, hepatocytes undergo dynamic organelle remodeling-particularly within mitochondria, the endoplasmic reticulum (ER), and peroxisomes-to orchestrate lipid oxidation, storage, and detoxification. These processes are tightly regulated by transcriptional programs involving nuclear receptors (e.g., PPARα, HNF4α, LXR) and stress-responsive signaling pathways (e.g., ATF6, XBP1, CHOP). While these adaptive networks maintain metabolic balance under stress, their dysregulation drives hepatic dysfunction in metabolic disease. Elucidating the molecular crosstalk and regulatory mechanisms that govern this shift from adaptation to dysfunction is essential to understanding the pathogenesis of liver disease in metabolic disorders. This review highlights the molecular mechanisms underlying adipose-liver communication, the role of organelle plasticity in hepatic lipid metabolism, and the transcriptional circuits that integrate these responses.