GPAM mediates mitochondrial dysfunction and the progression of alcoholic liver disease through lipid remodeling

Lipid metabolic disorders and mitochondrial dysfunction are key and core pathological processes that contribute to the progression of alcoholic liver disease (ALD). However, the effects of lipid metabolism disorders on mitochondrial dysfunction in patients with ALD remain unknown. Here, we demonstrated that glycerol-3-phosphateacyltransferase (GPAM) expression was down-regulated in patients with ALD and associated with ALD progression. Dysregulation of GPAM, a triglyceride synthetase, reshaped lipid metabolism by increasing the levels of toxic lipids such as ceramide and lysophosphatidylcholine and reducing the levels of mitochondrial structural lipids such as cardiolipin. These changes resulted in abnormal mitochondrial dynamics, impaired mitophagy, and dysfunctional mitochondrial respiration, which induced activation of the cGAS-STING pathway. This activation resulted in the accumulation of inflammatory infiltrates, triggering the ALD process in mice. However, the reexpression of GPAM in vivo and in vitro and in hepatic organoids alleviated the development of ALD. This study aimed to determine whether GPAM is a potential therapeutic agent and assess the close relationship between lipid metabolism disorders and mitochondrial dysfunction in patients with ALD.