The Impact of Ketogenic Diet on Lipid Metabolism: Insights from Genetically Diverse Mouse Models and Human Data

Abstract

Ketogenic diets (KD) have garnered considerable interest in recent years due to their potential therapeutic benefits across various health conditions. Characterized by high fat intake, moderate protein consumption, and very low carbohydrate levels, KD aims to induce a state of nutritional ketosis. Despite growing popularity, the underlying mechanisms and differential responses to KD remain incompletely understood, particularly concerning its impact on lipid metabolism and cardiovascular health markers. This study aims to elucidate these aspects. Genetically diverse outbred mice provide a valuable model for studying genetic variation under controlled dietary and environmental conditions. Using machine learning methods, we examined clinical and morphometric factors associated with serum cholesterol levels in 840 genetically distinct Diversity Outbred (DO) male and female mice. The mice were fed either a standard chow diet or a high-fat, high-sucrose diet. We found that the third strongest predictor of elevated cholesterol was serum calcium which correlated with serum cholesterol across both diets and sexes (r=0.39-0.48) in both Diversity Outbred (p=3.0 x 10-43) and BXD (p=0.005) mice. This finding aligns with human studies linking calcium levels to cholesterol and cardiovascular risk. As the KD has attracted attention for its potential benefits in weight loss, health enhancement, and athletic performance, responses to KD vary widely among individuals, and the regulation of ketolysis—ketone body breakdown—is not fully understood. In our study, we investigated how mTORC1 activation and KD influence ketone body disposal in muscle using Tsc1 knockout (KO) mice, inbred A/J mice, and DO mice. Tsc1 KO mice showed enhanced ketone body clearance where surprisingly, KD-fed did not improve ketone body disposal in A/J mice; instead, it reduced disposal by an average of approximately 25%. This was accompanied by reduced expression of ketolytic genes. Exploratory analyses hinted at potential correlations between ketone body disposal, cholesterol levels, and weight gain on KD, suggesting nutritional and genetic factors influence these relationships and contribute to individual variability in KD response. KDs shift the body's primary energy source from carbohydrates to fats. Despite their efficacy in weight loss and glycemic control, their effects on cholesterol remain unclear, especially in individuals with high baseline levels. This study examined whether individuals with elevated baseline cholesterol are more susceptible to increased cholesterol levels on a ketogenic diet. A meta-analysis of 22 studies involving 463 participants revealed an average LDL cholesterol increase of 9.7 mg/dl post-diet, with no significant correlation between baseline LDL and changes in LDL cholesterol observed. Further analysis, including genetically diverse DO mice, supported these findings, indicating no positive association between baseline and post-diet cholesterol levels. Exploratory regression tree analysis identified baseline LDL, HDL, and triglycerides as predictors of LDL-C change, with lower baseline levels correlating with greater LDL-C increases. These results suggest that the impact of a ketogenic diet on cholesterol levels may be independent of baseline cholesterol levels, underscoring the need for continued research to optimize dietary recommendations. Our work underscores the complex interplay between KDs and metabolic responses, highlighting the varied effects on lipid profiles and other phenotypic outcomes. Our findings suggest that a KDs impact on cholesterol levels may vary widely among individuals, independent of baseline lipid profiles. Future research should focus on elucidating the underlying mechanisms governing these differential responses to optimize the therapeutic potential and safety profile of ketogenic diets in diverse populations.