DDR2 ameliorates nonalcoholic hepatic steatosis by activating the AMPK/ACC pathway.

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD), also termed non-alcoholic fatty liver disease (NAFLD), represents the predominant chronic hepatic condition globally, yet remains without successful drug-based interventions. Understanding the molecular mechanisms driving MASLD progression is crucial. DDR2, a recently identified receptor tyrosine kinase, participates in various physiological processes including extracellular matrix remodeling, cell adhesion, and fibrosis. Given that MASLD pathogenesis involves lipid accumulation, inflammation, and progressive fibrotic remodeling of the liver, DDR2 signaling may play a critical role in linking extracellular matrix dynamics to metabolic and inflammatory pathways. However, its precise contribution to MASLD development and progression remains undefined, underscoring the need for mechanistic studies to clarify DDR2's role and potential as a candidate modulator. DDR2 expression was assessed in liver tissues from both hepatic steatosis and genetically obese mice. RT-qPCR, Western blotting, and Oil Red O staining were utilized to examine DDR2's role in lipid synthesis within hepatocytes under both cellular and animal models. The impact of DDR2 on MASLD were examined by utilizing db/db mice alongside C57BL/6J mice fed a high-fat diet (HFD). Hepatic DDR2 expression was markedly diminished in HFD-fed and db/db mice relative to controls. DDR2 overexpression resulted in diminished hepatic triglyceride accumulation and downregulated lipid synthesis-related gene expression in vitro and in vivo, whereas DDR2 knockdown exhibited the opposite effect. Mechanistically, DDR2 overexpression enhanced AMPK/ACC phosphorylation in hepatocytes, while its knockdown suppressed these pathways, findings corroborated by the use of AMPK inhibitors and agonists. DDR2 suppresses hepatocyte lipogenesis via activation of the AMPK/ACC pathway, suggesting its prospective role as a potential regulator in MASLD management.