Interrelationship between alcohol consumption, overnutrition, and pharmacotherapy for liver steatosis: Considerations and proposals.

Alcoholism and overnutrition both contribute to the development of hepatic steatosis in humans. In alcoholic liver disease, steatosis is driven by (i) alcohol oxidation via alcohol dehydrogenase (ADH), which increases the NADH/NAD+ ratio, and (ii) induction of cytochrome P450 2E1 (CYP2E1), which elevates oxidative stress. Both pathways generate toxic acetaldehyde. Overnutrition is characterized by excessive energy intake, high consumption of refined carbohydrates and saturated fatty acids (FAs), and low intake of dietary fiber, fruits, vegetables, and n-3 polyunsaturated fatty acids (n-3 PUFAs). The increased NADH/NAD+ ratio inhibits the Krebs cycle and FA β-oxidation, redirecting acetyl-CoA toward de novo lipogenesis. This process is mainly regulated by insulin-mediated activation of sterol regulatory element-binding protein-1c (SREBP-1c) and suppression of peroxisome proliferator-activated receptor-α (PPAR-α) related to n-3 PUFA depletion, which further impairs FA β-oxidation and upregulates citrate carrier expression, promoting lipogenesis. Chronic exposure to either alcohol or overnutrition independently promotes steatosis; however, co-exposure significantly exacerbates the condition, as shown in emerging preclinical studies. In humans, the relationship remains complex and inconsistent. Several anti-steatotic agents have been explored, including n-3 PUFAs, vitamins (E, C, D), polyphenols (curcumin, resveratrol, anthocyanins), anti-craving medications (disulfiram, naltrexone, nalmefene, acamprosate), and appetite suppressants (e.g., topiramate), as well as combination therapies such as naltrexone with bupropion. Despite the range of available interventions, inconsistent outcomes in past clinical trials hinder the establishment of standardized protocols. This underscores the urgent need to investigate synergistic effects of combined risk factors to better guide therapeutic strategies for hepatic steatosis prevention and reversal, and inform the health professionals on these aspects.