Adipose‑Liver Lipolysis Axis as a Metabolic Regulatory Hub
The review by Zhang et al. synthesises current knowledge on how free‑fatty‑acid flux from adipose tissue to liver coordinates lipid oxidation, storage and lipoprotein production, and how chronic lipolysis in obesity overwhelms hepatic capacity, contributing to metabolic‑associated steatotic liver disease.
Study and findings
Zhang and colleagues provide a narrative synthesis of experimental and clinical literature describing the adipose‑liver axis. They outline how, during fasting, adipocyte lipolysis releases free fatty acids (FFAs) that are taken up by hepatocytes for β‑oxidation, ketone‑body synthesis, triglyceride assembly and very‑low‑density lipoprotein (VLDL) secretion. The authors then contrast this physiological state with obesity and insulin resistance, where sustained lipolysis generates a chronic excess of FFAs that exceeds hepatic processing capacity, promoting lipid accumulation, lipotoxicity and inflammatory signaling characteristic of metabolic‑associated steatotic liver disease (MASLD).
Clinical interpretation
The review highlights that the balance between adipose‑derived FFA supply and hepatic organelle adaptability—particularly mitochondrial, endoplasmic reticulum and peroxisomal remodeling—determines whether the liver can maintain metabolic homeostasis or progress to dysfunction. Transcriptional regulators such as PPARα, HNF4α and LXR, together with stress‑responsive pathways (ATF6, XBP1, CHOP), orchestrate these adaptive responses. Dysregulation of these networks in the setting of chronic lipolysis may therefore represent a mechanistic link between excess adiposity and MASLD, suggesting that therapeutic strategies aimed at modulating adipose lipolysis or enhancing hepatic organelle plasticity could influence disease trajectory.
Limitations and open questions
Because the article is a narrative review, its conclusions are drawn from heterogeneous pre‑clinical and clinical studies without systematic appraisal of study quality or quantitative synthesis. Consequently, the extent to which observed molecular pathways operate in humans with MASLD remains uncertain. Key unanswered questions include: which specific lipolysis‑modulating interventions can safely restore the FFA‑liver balance; how organelle‑targeted therapies might be translated into clinical practice; and whether individual variability in nuclear‑receptor signaling predicts response to such approaches. Controlled mechanistic trials are needed to test these hypotheses.
Source
Zhang S, Cedillo L, Villanueva CJ. Lipolysis-Driven Communication Between Adipose Tissue and Liver: A Key Axis in Metabolic Regulation. J Lipid Res. 2026 Sep 24;doi:10.1016/j.jlr.2026.101150.