(OR27-01-24) Effect of Long-Term Consumption of a Ketogenic Diet on the Progression of Metabolic Dysfunction-Associated Fatty Liver Disease in Mice

Objectives: Imbalances in dietary macronutrient ratios can disrupt host metabolism and promote the development of metabolic dysfunction-associated fatty liver disease (MAFLD). This study investigated whether disproportionate macronutrient ratios alter metabolism and contribute to the development of MAFLD. It further examined the therapeutic potential of diets containing varying levels of carbohydrate (CHO) and fat on reversing MAFLD.

Methods: Four-week-old male wildtype (WT) mice (C57BL6) were assigned diets with distinct CHO and fat proportions for 16 weeks. The diets were (1) HCD, high CHO (kcal%, CHO/fat/protein: 70/11/18), (2) HFD, high fat (42/40/18); (3) KD, ketogenic diet, very low in CHO and very high fat (2/80/18). An additional two groups maintained on HFD for 8 weeks were switched to either KD or HCD to assess their impact on established MAFLD. A chow-fed group was used as a basal control for the study. Weekly body weight, food intake, fasting blood glucose, liver function markers, and β-hydroxybutyrate (β-HB) levels were monitored at 2, 4, 8, and 16 weeks. Upon euthanasia, biochemical, hepatic gene expression, and histochemical analysis were used to assess MAFLD markers.

Results: Compared to the chow group, mice fed HFD and KD diets, but not HCD, developed MAFLD, characterized by obesity, hyperglycemia, insulin resistance, hyperlipidemia, hepatic steatosis, and liver dysfunction. In support, both HFD and KD groups, but not the HCD group, exhibited elevated hepatic mRNA levels of inflammatory and lipogenic genes, along with reduced mRNA transcripts of energy homeostasis genes. Notably, the KD group had elevated serum and hepatic β-HB levels, indicating ketogenesis. Findings from the chronic feeding cohort suggest that high-fat diets, including KD, contribute to MAFLD despite inducing ketogenesis. Remarkably, therapeutic intervention with either HCD or KD diets attenuated metabolic syndrome, hepatic steatosis, and inflammation in the group with pre-existing MAFLD.

Conclusions: Overall, this study suggests that chronic consumption of high fat, but not high carbohydrate, diets drive the development of MAFLD. However, therapeutic intervention with a ketogenic diet can reverse MAFLD.

Funding Sources: Career Development Award [ID# 597229] from the Crohn’s & Colitis Foundation (CCF) to V.S.