Lean metabolic dysfunction-associated steatotic disease is reversed by betulinic acid, a therapeutic triterpene from birch bark

Abstract

The prevalence of metabolic dysfunction-associated steatotic disease (MASLD) in lean individuals has continued to increase. Despite the benefits of betulinic acid in obesity, its role in lean MASLD has not been verified. We investigated whether betulinic acid recovered lean MASLD by rescuing lipid homeostasis in vivo. Lean MASLD disease mice model was established using atherogenic diets on C57BL/6 male mice. Betulinic acid (5, 15, and 25 mg/kg bw) or positive control was provided ad libitum for 12 weeks. Betulinic acid reduced body adiposity (p < 0.01) without affecting lean mass. Betulinic acid improved hepatic lipid accumulation (p < 0.01). Blood lipid profiles, including triglyceride, total cholesterol, LDL-cholesterol, and non-esterified fatty acids (p < 0.001 and p < 0.05), were decreased by betulinic acid. RNA transcriptomes and immunoblotting revealed that betulinic acid markedly reduced hepatic de novo lipogenesis by inhibiting Srebp1/Acc/Fas (p < 0.05). Betulinic acid increased fatty acid utilization (p < 0.05) in skeletal muscle by stimulating Ampk/Acc1/Cpt1. These findings imply that betulinic acid is a potent bioactive compound that prevents lean MASLD and dyslipidemia.