ALD metabolism, atheroscleros and cardiovascular risk
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 mechanisms underlying MetALD and their impact on cardiovascular disease (CVD)—the leading cause of SLD mortality—remain elusive, we investigated how metabolic dysregulation and alcohol intake synergistically contribute to 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 investigate the contribution of ethanol-induced dysbiosis. Associations between alcohol consumption and cardiometabolic risk factors were assessed in two independent human cohorts (n = 5115 and 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. Liver transcriptomic profiling revealed ethanol-induced alterations in lipid metabolism and enhanced pro-inflammatory signatures, accompanied by increased recruitment of Ly6Chigh monocytes to the liver and elevated Ly6Chigh monocytes in circulation. Correspondingly, ethanol-consuming HFC diet-fed Ldlr-/- mice developed enlarged aortic root lesions. Neither germ-free conditions nor antibiotic treatment mitigated CVD progression. Metabolomic profiling revealed hyperuricemia in ethanol-exposed HFC diet-fed Ldlr-/- mice, coinciding with upregulated NLRP3 inflammasome activation-related gene expression in both liver and aortic root. Notably, human data mirrored these findings, demonstrating a dose-dependent association between alcohol intake, dyslipidemia, monocytosis, hyperuricemia, and increased cardiovascular risk.  Conclusion: Our findings identify alcohol as an important immune-modulatory lifestyle factor that contributes to elevated cardiovascular risk.
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 mechanisms underlying MetALD and their impact on cardiovascular disease (CVD)—the leading cause of SLD mortality—remain elusive, we investigated how metabolic dysregulation and alcohol intake synergistically contribute to 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 investigate the contribution of ethanol-induced dysbiosis. Associations between alcohol consumption and cardiometabolic risk factors were assessed in two independent human cohorts (n = 5115 and 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. Liver transcriptomic profiling revealed ethanol-induced alterations in lipid metabolism and enhanced pro-inflammatory signatures, accompanied by increased recruitment of Ly6Chigh monocytes to the liver and elevated Ly6Chigh monocytes in circulation. Correspondingly, ethanol-consuming HFC diet-fed Ldlr-/- mice developed enlarged aortic root lesions. Neither germ-free conditions nor antibiotic treatment mitigated CVD progression. Metabolomic profiling revealed hyperuricemia in ethanol-exposed HFC diet-fed Ldlr-/- mice, coinciding with upregulated NLRP3 inflammasome activation-related gene expression in both liver and aortic root. Notably, human data mirrored these findings, demonstrating a dose-dependent association between alcohol intake, dyslipidemia, monocytosis, hyperuricemia, and increased cardiovascular risk.  Conclusion: Our findings identify alcohol as an important immune-modulatory lifestyle factor that contributes to elevated cardiovascular risk.
Medical University of Vienna