Alcohol intake reprograms hepatic immune-metabolic circuits to exacerbate murine atherosclerosis and human cardiovascular risk

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Background and Aims Recent reclassification of steatotic liver disease (SLD) distinguishes metabolic dysfunction-associated steatotic liver disease (MASLD) from MetALD, a newly defined entity combining MASLD with alcohol consumption. Since the mechanisms linking alcohol consumption in the context of SLD to cardiovascular disease (CVD), the leading cause of SLD mortality, remain elusive, we investigated how metabolic dysregulation and alcohol intake synergistically promote atherosclerosis. Methods Low-density lipoprotein receptor-deficient ( Ldlr -/- ) mice were fed a high-fat, high-cholesterol (HFC) diet with regular or ethanol-containing drinking water (10–20% v/v). Germ-free and antibiotic-treated Ldlr -/- mice were used to assess the contribution of ethanol-induced dysbiosis. Associations between alcohol consumption and cardiometabolic risk were assessed in two human cohorts ( N = 5115, N = 2515). Results Ethanol intake in HFC diet-fed Ldlr -/- mice exacerbated hepatic steatosis and systemic dyslipidemia, despite only modest elevations in systemic ethanol levels ( p s≤0.05). Liver transcriptomic profiling revealed ethanol-induced alterations in lipid metabolism and enhanced proinflammatory signatures, accompanied by increased recruitment of Ly6C high monocytes to the liver ( p =0.0121) and elevated levels in circulation ( p =0.0043). Correspondingly, ethanol-consuming HFC diet-fed Ldlr -/- mice developed enlarged aortic root lesions ( p =0.0105). Neither germ-free conditions nor antibiotic treatment mitigated CVD progression. Metabolomic profiling revealed hyperuricemia in ethanol-exposed HFC diet-fed Ldlr -/- mice, which was associated with an upregulation of inflammasome-related genes in the liver, along with an increase in hepatic NLRP3 protein expression ( p s≤0.05). Notably, human data mirrored these findings, demonstrating a dose-dependent association between alcohol intake, dyslipidemia, monocytosis, hyperuricemia, and increased cardiovascular risk ( p s≤0.05). Conclusion Our findings identify alcohol as an important immune-modulatory lifestyle factor that contributes to elevated cardiovascular risk. Impact and Implications Alcohol consumption, even at moderate levels, contributes to cardiovascular risk, particularly in individuals with SLD. Combining murine models with human cohort data, we show that alcohol intake in SLD is associated with coordinated immune-metabolic alterations, including dyslipidemia, monocytosis, hyperuricemia, and enhanced NLRP3 inflammasome signaling, collectively indicating an elevated cardiovascular risk profile. These findings are relevant to hepatology and cardiovascular medicine, linking alcohol consumption to measurable systemic pathways beyond liver injury. Clinically, systematic assessment of alcohol intake and incorporation into cardiovascular risk evaluation may improve risk stratification and support closer surveillance and preventive strategies in patients with SLD.

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