D-allulose attenuates dyslipidemia, oxidative stress, and inflammation in high-fat-diet-induced metabolic dysfunction-associated steatotic liver disease in rats

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a diet-related metabolic disorder characterized by hepatic lipid accumulation, dyslipidemia, insulin resistance, oxidative stress, and chronic inflammation, highlighting the need for safe nutritional interventions. This study evaluated the antihyperlipidemic, antioxidant, and anti-inflammatory effects of D-allulose, alone or in combination with dorsomorphin, in a high-fat diet (HFD)-induced rat model of Metabolic dysfunction-associated steatotic liver disease (MASLD). Forty-eight male Wistar rats were allocated to a control diet group, an HFD group, or an HFD group treated orally with D-allulose (0.3 or 0.6 g/kg) with or without dorsomorphin (0.2 mg/kg) orally for 12 weeks. Omnibus 𝑝-values for the 22 biochemical endpoints were subjected to a retrospective Benjamini–Hochberg false-discovery-rate sensitivity analysis. HFD feeding induced weight gain, dyslipidemia, hepatic injury, oxidative stress, inflammation, and hyperinsulinemia. D-allulose dose-dependently ameliorated these disturbances, reducing atherogenic lipids, lipid peroxidation, inflammatory cytokines, and insulin while improving antioxidant status. Notably, TG decreased from 164.51 mg dL −1 in HFD rats to 113.52 and 99.43 mg dL −1 with low- and high-dose D-allulose, respectively, while LDL-C decreased from 86.45 to 53.19 and 49.24 mg dL −1 ; HDL-C remained unchanged. D-allulose also attenuated HFD-induced hepatic steatosis, degeneration, necrosis, inflammation, and early fibrosis, and this histological protection was maintained or enhanced by dorsomorphin co-administration. A retrospective FDR sensitivity analysis supported the principal lipid, antioxidant, inflammatory, and insulin findings, whereas the ALT and FBG findings did not remain significant and were considered exploratory. The combination groups generally matched or outperformed D-allulose alone across several biochemical and histological endpoints. However, because dorsomorphin is a non-selective AMPK/BMP inhibitor and AMPK activity was not directly measured, these findings do not establish AMPK’s mechanistic involvement. Overall, D-allulose shows promising protective impacts as a bioactive ingredient for obesity-related metabolic disorders.