Induction of Fructose Mediated De Novo Lipogenesis Coexists with the Upregulation of Mitochondrial Oxidative Function in Mice Liver.

Background: Dysfunctional mitochondrial metabolism and sustained de novo lipogenesis (DNL) are characteristics of metabolic dysfunction-associated steatotic liver disease (MASLD), a comorbidity of obesity and type 2 diabetes. Fructose, a common sweetener and a potent inducer of lipogenesis, contributes to the etiology of MASLD.

Objectives: Our goal was to determine whether higher rates of DNL, through its biochemical relationships with mitochondria, can contribute to dysfunctional induction of oxidative networks in the liver.

Methods: Male C57BL/6JN mice were given a low-fat (10% fat kcal, 49.9% corn starch kcal), high-fat (HF; 60% fat kcal), or HF/high-fructose diet (HF/HFr; 25% fat kcal, 34.9% fructose kcal) for 24 wk. In a follow-up study, mice on normal feed pellets were provided either 30% fructose in drinking water (FW) to induce hepatic DNL or regular water (NW) for 14 d. Hepatic mitochondria and liver tissue were used to determine oxygen consumption, reactive oxygen species (ROS) generation, tricarboxylic acid (TCA) cycle activity, and gene/protein expression profiles.

Results: Hepatic steatosis remained similar between HF and HF/HFr fed mice livers. However, lipogenic and lipid oxidation gene expression profiles and the induction of TCA cycle metabolism were all higher (P ≤ 0.05) in HF/HFr livers. Under fed conditions, the upregulation of DNL in FW livers occurred in concert with higher mitochondrial oxygen consumption (basal; 1.7 ± 0.21 compared with 3.3 ± 0.14 nmoles/min, P ≤ 0.05), higher ROS (0.87 ± 0.09 compared with 1.25 ± 0.12 μM, P ≤ 0.05) and higher flux through TCA cycle components P ≤0.05. Furthermore, TCA cycle activity and lipid oxidation remained higher during fasting in the FW livers P ≤ 0.05.

Conclusions: Our results show that fructose administration to mice led to the concurrent induction of mitochondrial oxidative networks and DNL in the liver. Sustained induction of both DNL and mitochondrial oxidative function could accelerate cellular stress and metabolic dysfunction during MASLD.