Excessive dietary fat and fructose enhance hepatic lipogenesis and impair mitochondrial dynamics to cause MASLD in C57BL/6 mice

OBJECTIVE: Metabolic dysfunction-associated steatotic liver disease (MASLD) affects around 1/3 of the worldwide population, with rising prevalence. Surplus fat and carbohydrate intake are crucial for MASLD onset. This study aimed to elucidate the interference of excess lipids and fructose (32 % as energy each), alone or in combination, on the hepatic energy metabolism of male mice. METHODS: Forty male C57BL/6 mice (3 months old) were randomly assigned to receive a control diet (C, 10 % of energy as soybean oil, n = 10), high-fat diet (HF, 32 % of energy as lard and 10 % as soybean oil, n = 10), high-fructose diet (HFRU, 32 % of energy as fructose, and 10 % as soybean oil, n = 10) or a diet rich in lipids and associated fructose (HF-HFRU, 32 % of energy as lard, 10 % as soybean oil, and 32 % of energy as fructose, n = 10) for 12 weeks. RESULTS: The increased consumption of saturated fat or fructose, isolated or in association, caused oral glucose intolerance, increased hepatic triacylglycerol and cholesterol, and enhanced the expression of proteins related to hepatic inflammation, lipogenesis, mitochondrial dysfunction, and ER stress, resulting in a marked increase in hepatic steatosis. CONCLUSION: Our results showed that high consumption of diets rich in lipids and fructose contributed to the development of MASLD and revealed an intimate relationship between altered mitochondrial dynamics and ER stress. Understanding the molecular pathways that regulate the accumulation of hepatic lipids can lead to promising therapies for MASLD.