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Updated: May 15, 2026
Quantification of Atherosclerosis in Mice
Published on: June 12, 2019
Hepatic GSTM3 deficiency Accelerates Atherosclerosis through redox-driven mitochondrial dysfunction and
Trina Roy1, Aleepta Guha Ray2, Subhamoy Pratihar3
1Cell Biology and Physiology Division, CSIR-Indian Institute of Chemical Biology, IICB TRUE Campus, CN-6, Sector 5, Salt Lake, Kolkata, 700091, WB, India; Academy of Scientific and Innovative Research (AcSIR), Sector 19, Kamala Nehru Nagar, Ghaziabad, 201002, India.
Background And Aims:
Metabolic dysfunction-associated steatotic liver disease (MASLD) is closely associated with accelerated atherosclerosis and cardiovascular complications, yet the hepatic redox-dependent mechanisms linking cholesterol overload to systemic vascular risk remain poorly defined. Glutathione S-transferase mu 3 (GSTM3) is a lipid peroxide-detoxifying enzyme within the hepatic antioxidant defense system, but its role in oxidative stress-induced dyslipidemia and associated atherogenesis is unknown.
Methods:
In this study we integrated GSTM3-interactome profiling, hepatocyte-specific GSTM3 silencing, and in vivo GSTM3 knockdown in hypercholesterolemic Apoe-/- mice to determine if GSTM3 regulates hepatic redox balance, mitochondrial homeostasis, and atherosclerosis progression under cholesterol overload.
Results:
High-cholesterol feeding induced a biphasic hepatic GSTM3 response followed by depletion during sustained injury, coinciding with heightened steatohepatitis and plaque formation. GSTM3 knockdown in hepatocytes amplified cholesterol-induced oxidative stress, disrupted mitochondrial biogenesis and dynamics, and promoted necroinflammatory cell death. In Apoe-/- mice, hepatic GSTM3 loss markedly worsened glutathione depletion (∼55%, p < 0.0001) and lipid peroxidation (∼2-fold, p < 0.0001), with enhanced fibrogenesis and inflammasome activation. These hepatic alterations were associated with a more atherogenic lipid profile and significantly increased aortic plaque burden (∼24.8%, p < 0.01) compared with hypercholesterolemic controls.
Conclusion:
Hepatic GSTM3 functions as a redox gatekeeper that preserves mitochondrial integrity and restrains necroinflammation during cholesterol overload. Loss of GSTM3 drives redox-induced mitochondrial dysfunction and systemic oxidative dysregulation, thereby accelerating atherogenesis. These findings identify hepatic redox buffering capacity as a determinant of cardiovascular risk in metabolic disease.
