High-protein diets and metabolic dysfunction-associated steatotic liver disease: A double-edged sword in liver health

Figure 1 Comparative effects of dietary patterns on hepatic metabolism, inflammation, and metabolic dysfunction-associated steatotic liver disease risk. The Western diet, characterized by high intake of ultra-processed foods, red meat, and added sugars, exacerbates hepatic steatosis, glucose intolerance, and bodyweight gain. This dietary pattern promotes proinflammatory cytokine release, nuclear factor kappa B signaling, and toll-like receptor 4-mediated inflammation, leading to oxidative stress, liver stiffness, and fibrosis. The high-fat/high-fructose diet rapidly increases blood glucose and bodyweight, inducing metabolic dysfunction and hepatic pathology. Consequently, the risk of metabolic dysfunction-associated steatohepatitis and hepatocellular carcinoma is markedly increased. In contrast, the Mediterranean diet, rich in monounsaturated fatty acids, omega-3 fatty acids, and polyphenols from nuts, fruits, vegetables, legumes, and fish, enhances insulin sensitivity and reduces hepatic lipid accumulation. Intermittent fasting (5:2 regimen) further augments these protective effects by upregulating phosphoenolpyruvate carboxykinase 1 and peroxisome proliferator-activated receptor alpha, thereby suppressing oxidative damage, inflammatory signaling, and postprandial hyperglycemia. PPARα: Peroxisome proliferator-activated receptor alpha; PCK1: Phosphoenolpyruvate carboxykinase 1; TSC: Tuberous sclerosis complex; AA: Amino acid; mTORC: Mechanistic target of rapamycin complex; MASH: Metabolic dysfunction-associated steatohepatitis; HCC: Hepatocellular carcinoma; NK-κB: Nuclear factor kappa B; TLR4: Toll-like receptor 4; MASLD: Metabolic dysfunction-associated steatotic liver disease; PI3K: Phosphatidylinositol 3-kinase; AKT: AKR mouse thymoma kinase; Rag: Ras-related GTP-binding protein; SLC38A: Solute carrier family 38 member A.