The Effect Of Ketogenic Diet On Hepatic Cholesterol Metabolism

The ketogenic diet (KD), known for its high-fat, low-carbohydrate composition, has gained popularity for weight loss and metabolic health benefits. Despite these advantages, there are concerns that the diet's high saturated fat content might elevate cholesterol levels and cardiovascular disease (CVD) risk. This study investigates the KD's impact on the molecular mechanisms of cholesterol metabolism in the liver, focusing on cholesterol synthesis markers such as 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase) and sterol regulatory element-binding protein-2 (SREBP-2), as well as cholesterol uptake markers including proprotein convertase subtilisin/kexin type 9 (PCSK9) and LDL receptors (LDLr). For that, male Wistar rats (n = 6 per group) were fed for 16 weeks one of the following diets: standard chow (SC, 60% carbohydrates, 13% fat, 27% protein), high-fat sucrose-enriched (HFS, 20% carbohydrates, 60% fat, 20% protein), and ketogenic diet (KD, 0% carbohydrates, 80% fat, 20% protein). Liver tissue was extracted and analyzed for gene expression using real-time PCR and protein content using western blotting. Blood samples were collected to measure circulating cholesterol levels. We found that neither plasma cholesterol levels nor HMG-CoA reductase and SREBP-2 levels in the liver differed among the dietary interventions. However, the KD significantly reduced liver PCSK9 content and expression in comparison other diets, suggesting that the KD enhanced clearance of circulating cholesterol by the liver. To test whether there was a higher amount of LDLr on the membrane compared to the cytoplasm, the ratio of LDLr distribution between these compartments was measured. Importantly, there was an upward trend in the levels of LDLr on the membrane. In conclusion, the KD altered key steps that regulate hepatic cholesterol metabolism and prevented plasma cholesterol levels from increasing, despite its elevated saturated fat content.