Amelioration of hepatic steatosis in male obese rats by high-protein diet is dependent upon protein source.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by triglyceride accumulation and insulin resistance. Currently, weight loss remains the primary strategy for reducing liver fat. High-protein diets (HPDs) may improve metabolism, lower body weight, and reduce hepatic fat; however, the effects of specific protein sources are largely unknown. This study examines the effects of HPDs from animal and plant protein sources, separately and in combination, on hepatic steatosis and MASLD-related metabolic pathways. Obese fa/fa Zucker male rats received HPDs (35% kcal from protein) containing egg white, plant (soy+pea protein, 1:1), mixed (egg white+soy+pea protein, 2:1:1), or casein (HPcasein) as the protein sources, or a normal protein diet (15% kcal from protein) containing casein, for 8 weeks. HPplant and HPmixed diets increased body weight by 1.2-fold versus HPcasein. HPDs containing egg white, plant or mixed protein sources reduced the liver-body weight ratio by ∼30% and liver triglycerides by ∼50% compared to the casein diets. These changes were linked to smaller lipid droplets, less fibrosis, and decreased lipid peroxidation in liver. HPDs containing egg white, plant or mixed protein increased markers of VLDL synthesis (ApoB-100, MTP) via ChREBP. These diets also lowered HOMA-IR, and reduced HMGCS2 (ketogenesis marker). In conclusion, HPDs containing egg white or plant proteins reduced hepatic steatosis and indices of insulin resistance, unconnected to body weight. Determining the effects of specific protein sources in HPDs is an important consideration for further research on MASLD management.