(OR23-06-24) Soluble Fiber-Supplemented Ketogenic Diet Attenuated Hepatic Lipid Accumulation and Inflammation

Objectives: Interventions with ketogenic diets (KDs) containing very high fat and low carbohydrate have shown mixed results for metabolic disorders, including metabolic dysfunction-associated fatty liver disease (MAFLD). Prebiotic fiber, such as inulin, is known to improve metabolic syndrome and hepatic steatosis. Therefore, we aimed to investigate whether incorporating inulin into a KD could enhance its efficacy in attenuating MAFLD.

Methods: For assessing the effect of fiber-supplemented KD (KD-F) on the progression of MAFLD, C57BL6 wild-type (WT) male mice (4 weeks old, n = 6-8/group) were maintained on KD (kcal%, carbohydrate (CHO)/fat/protein: 2/80/18) or KD-F (KD with added inulin, 6.5 gram % w/v) for 16 weeks. To investigate the effectiveness of both KD and KD-F in improving pre-existing MAFLD, we employed a high-fat diet (HFD, CHO/fat/protein: 42/40/18)-induced MAFLD model. Specifically, four-week-old WT mice were first fed HFD for 8 weeks, followed by a switch to KD and KD-F for another 8 weeks. In addition to weekly body weight, markers of insulin resistance, hyperlipidemia, liver function, steatosis, inflammation, lipogenesis, and energy homeostasis were monitored to assess MAFLD.

Results: To our surprise, compared to the basal control group, the KD group promoted metabolic and liver dysfunction. Remarkably, the KD-F group exhibited improved MAFLD, characterized by attenuation of body weight gain, improved insulin sensitivity, and reduced serum levels of lipids and liver function markers (ALT and AST). H&E staining revealed reduced hepatic lipid accumulation and adipocyte hypertrophy in KD-F-fed mice compared to the KD group. Furthermore, the KD-F group showed reduced hepatic expression of lipogenic genes (Srebp1c, Scd1, Scd2, Fas) and inflammatory genes (Il1β, Il6, Mcp1, and Tnfα), while expression of energy expenditure-related genes (Pparα, Pparβ, Sirt1, and Cpt1) was increased. Importantly, the KD-F diet also demonstrated superior efficacy in both reversing MAFLD and reducing hepatic inflammation compared to the KD group.

Conclusions: Our findings demonstrate the potential benefit of soluble fiber supplementation in enhancing the therapeutic efficacy of ketogenic diets for mitigating MAFLD.

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