Fettleber und Wein: Warum Alkohol bei Stoffwechselrisiken schwerer wiegt

Metabolic dysfunction-associated fatty liver disease (MASLD) is associated with severe forms of liver injury, including fibrosis and cirrhosis. The main risk factors for MASLD-obesity, type 2 diabetes mellitus (T2DM), dyslipidemia, and insulin resistance (IR)-contribute to metabolic disturbances that initiate hepatic steatosis. Metabolic and alcohol-related liver disease (MetALD) describes patients with MASLD who also present alcohol-associated hepatic injury. Chronic oxidative and inflammatory stress promotes the progression of steatosis in both conditions. T2DM and chronic alcohol consumption are independent lifestyle-related risk factors for cirrhosis within the spectrum of metabolic dysfunction-related liver disease (MASLD and MetALD). The coexistence of both conditions may exacerbate hepatic pathological alterations. IR, which is frequently observed in patients with cirrhosis, can lead to the development of a condition known as hepatogenic diabetes (HD). HD is characterized by hyperinsulinemia, IR, and β-cell dysfunction occurring during the onset of cirrhosis and is associated with hepatic inflammation even in the absence of traditional metabolic risk factors such as obesity or a prior history of T2DM. In this context, alcohol intake enhances lipolysis in peripheral tissues, promotes hepatic steatosis, and aggravates metabolic dysfunction, ultimately contributing to excessive mitochondrial production of reactive oxygen species (ROS). Therefore, the present review examin

<h4>Background & aims</h4>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.<h4>Methods</h4>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 = 5,115, n = 2,515).<h4>Results</h4>Ethanol intake in HFC diet-fed Ldlr^-/- mice exacerbated hepatic steatosis and systemic dyslipidemia, despite only modest elevations in systemic ethanol levels (p values ≤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 the circulation (p = 0.0043). Correspondingly, ethanol-consuming HFC diet-fed Ldlr^-/- mice

With the increasing prevalence of alcohol-related diseases, expanding our understanding of the toxic effects of excessive alcohol consumption is critical for prevention and treatment of metabolic and inflammatory pathology. This review summarizes current knowledge on the metabolic dysfunction and inflammation caused by alcohol and their impact on the pathogenesis of alcohol-related liver disease (ALD), type 2 diabetes, cardiovascular disease, and obesity, and neurological damage. It highlights recent evidence that alcohol induces a cascade of reactive oxygen species (ROS)-mediated lipid peroxidation and nicotinamide adenine dinucleotide (NAD⁺) depletion, triggering mitochondrial dysfunction and metabolic imbalances in the liver, heart, pancreas, and brain. By integrating these mechanistic insights with emerging data on how disrupted lipid and glucose metabolism amplify immune dysregulation, the review underscores the interplay between metabolic and inflammatory pathways in exacerbating tissue injury across these organs. A deep understanding of these metabolic and inflammatory disruptions is therefore essential for developing novel therapeutic strategies, including metabolic and nutritional interventions, aimed at mitigating the health risks of excessive alcohol consumption.