Overview

Obesity has become a major chronic disease in the United States with a reported prevalence of 42.4% between 2017-2018. Its prevalence has given rise to related problems such as heart disease, stroke, type 2 diabetes, certain types of cancer, and premature death. In 2008, the estimated annual medical cost of obesity in the US was 147 billion dollars. The medical cost of people with obesity was $1,429 higher than those with normal weight (CDC, 2021). Exercise, diet, and behavior-change are strategies to control weight gain and keep body mass index (BMI) within the normal range (18.5-25 kg/m2). Various weight-loss diets claim to achieve this purpose. Among them, the ketogenic diet has demonstrated success as a weight management strategy (Drabińska et al., 2021). Despite this benefit, recent studies have shown that the ketogenic diet increases low density lipoprotein (LDL) cholesterol. This is a concern give the association of LDL cholesterol and heart disease. This mini review highlights recent findings on the effect of the ketogenic diet on LDL cholesterol levels. A review of the ketogenic pathway is first presented to give the reader an appreciation of the biochemistry behind the ketogenic diet.   

Ketogenesis Pathway

The ketogenic diet is a type of diet containing high fat (75% to 90%), moderate protein (10%) and very low carbohydrates (5%) (Anekwe et al., (2019). Low carbohydrates promote release of glucagon which leads to increased fatty acid supply to the liver, and hence high beta-oxidation (Adam et al., 2006). Increased fat burning produces more acetyl-CoA, a molecule that is typically sent to the citric acid cycle for subsequent ATP production. However, under low carbohydrate conditions, the liver diverts oxaloacetate to gluconeogenesis. The redirection of this important intermediate prevents the citric acid cycle from moving forward efficiently. This causes a buildup of acetyl-CoA which gets directed to the ketogenesis pathway to make ketone bodies (acetone, acetoacetate, and β-hydroxybutyrate). These are alternate energy-molecules that tissues (including the brain) can use when glucose is low.  

Tansey (2020) provides an excellent overview of the ketogenesis pathway (figure 1). In the first step, two molecules of acetyl-CoA combine to form acetoacetyl-CoA using the enzyme thiolase. A molecule of CoA is released in the process. The second step is a rate-determining step. The acetoacetyl-CoA formed in the first step combines with another acetyl-CoA with the help of hydroxymethy-CoA synthase (HMG-CoA synthase) to produce β-hydroxy- β-methylglutaryl-CoA (HMG-CoA). In the third step, the first ketone body, acetoacetate, is formed. Here, HMG-CoA is cleaved by HMG-CoA lyase to release acetoacetate and acetyl-CoA. In step four, acetoacetate undergoes spontaneous degradation to produce acetone, or it may be reduced to D-3-hydroxybutyrate via an enzyme-catalyzed reversable pathway using β-hydroxybutyrate dehydrogenase.

After release from liver cells, ketone bodies enter the blood where they are carried to tissues such as the brain, heart and skeletal muscles to be metabolized for energy. Figure 2 illustrates the breakdown of ketone bodies for energy production. In the first step, β-hydroxybutyrate is converted to acetoacetate by β-hydroxybutyrate dehydrogenase while releasing one NADH. Acetoacetate then undergoes a substitution reaction with succinyl-CoA to form acetoacetyl-CoA and succinate. This reaction is facilitated by 3-ketoacyl-CoA transferase. The liver lacks this enzyme, which prevents it from using the ketone bodies that it produces. In the final reaction, acetoacyl-CoA reacts with CoA in the presence of thiolase to produce two molecules of acetyl-CoA. Acetyl-CoA can then be used in the citric acid cycle of the target cell to produce energy. 

Recent Evidence Showing Negative Effects of the Ketogenic Diet on LDL-Cholesterol

Harmon et al., (2020) screened blood lipid results of 1420 Mayo Clinic patients who had elevated LDL above 190 mg/dL. Five of these patients were selected for more careful study since they reported to have been on a keto diet. Three of the patients had a family history of early cardiovascular disease, and LDL cholesterol reaching 295% above the baseline. One patient struggled with severe anorexia nervosa and was 1081% above the baseline. The last of the five patients had a 159% increase in LDL cholesterol from the baseline despite intense statin treatment. A common characteristic of all five patients was a genetic disposition for hypercholesterolemia. Harmon et al., (2020) therefore concluded that patients with this genetic predisposition may be particularly at risk for high LDL cholesterol if they are on a ketogenic diet.  

Goldberg et al. (2020) described five patients who developed plasma cholesterol on ketogenic diets. Four of them had previous elevated lipid/cholesterol disease condition or familial hyperlipidemia, and experienced exacerbated hypercholesteremia on a ketogenic diet. However, one patient experienced dramatic increase in LDL cholesterol (<100 mg/dL to 243 mg/dL) despite having no family history of dyslipidemia or genetic mutation of the NPC1L1 gene. This gene is known to regulate cholesterol absorption (Harmon et al., 2020). Therefore, healthy individuals may also be at risk of elevated LDL cholesterol on a ketogenic diet. Buren et al. (2021) proved this. They investigated the effect of the ketogenic diet on LDL cholesterol in the blood of healthy, young, and normal-weight women. In the study, 24 women were assigned to a 4-week ketogenic diet (4% carbohydrates, 77% fat, 19% protein) followed by a control diet (44% carbohydrates, 33% fat, 19% protein). Treatments were separated by a 15-week “wash out period”. Upon blood lipid analysis following this period, all the women had elevated LDL cholesterol.

A rapid increase in LDL cholesterol after starting a ketogenic diet, followed by a rapid correction when it is discontinued, provides further evidence of the diet’s negative effect. For example, Anekwe et al. (2019) studied the case of a 56-year-old woman with class I obesity (BMI = 31.42 kg/m2) and a medical history with binge-eating, depression, anxiety and post-traumatic stress disorder. Laboratory testing revealed that she had an LDL cholesterol level of 156 mg/dL before she went on her self-imposed ketogenic diet. During the diet, her LDL cholesterol drastically increased to 216 mg/dl. After agreeing to quit the diet, her LDL cholesterol levels dropped to 209 mg/dL in just two weeks. Eight months later it was 157 mg/dL and was normal (80 mg/dL) after a year.

A similar outcome was observed by Noalin et al. (2020). They studied a 56-year-old Hispanic female with a medical history of hypertension and fibromyalgia. The patient reported that she had been following the ketogenic diet with daily exercise for 30-45 days prior to the start of the study. Her BMI was 28 kg/m2 (overweight), total cholesterol 283 mg/dL, and LDL cholesterol 199 mg/dL. She was instructed to stop the ketogenic diet and to adopt a balanced diet with higher amount of carbohydrates and less fat. After four weeks, her lipid profile showed a total cholesterol of 190 mg/dl, and LDL cholesterol of 106 mg/dL. This enabled her to end her reliance on statin therapy to manage her cholesterol.

Given that ketogenic diets are high in fat, one would suspect that the increase in LDL cholesterol  is due to increased saturated fats in the diet. So what would be the case when saturated fats are substituted with unsaturated fats? Guzel et al. (2016) answered this question by studying 320 epileptic children who experienced at least two seizures a week. They were fed a Mediterranean style ketogenic diet with extra virgin oil as the principal fat source (80-85% of total fat) for 12 months. Guzel et al. (2016) found that even with an olive oil-based diet, serum levels of total cholesterol, triglycerides and LDL cholesterol increased. LDL cholesterol jumped from a baseline of 106.2 mg/dL to 131.9 mg/dL within the first month of the study and then stabilized thereafter.  

Conclusion

The preceding studies demonstrate that the ketogenic diet drastically increase LDL cholesterol. Hence, adopting the ketogenic diet as a tool to lose weight may not be worth it. Some studies have shown no effect or increase in LDL cholesterol on a ketogenic diet (Hussain et al., 2012. Dashti et al., 2006). However, this may be due to variations in expression of the NPC1L1 and ABCG5/8 genes responsible for regulating cholesterol absorption. It may therefore be useful to complete genetic testing to determine potential predisposition for hypercholesterolemia before making the decision to start a keto diet. Physicians and dieticians should be cautious when recommending ketogenic diets to their patients without taking into consideration the need to monitor blood lipid profiles.

Figure 1. Ketogenesis pathway (Source: Tansey, 2020)

Figure 2. Breakdown of ketone bodies (Source: Tansey, 2020)

References

Adam-Perrot, A., Clifton, P., & Brouns, F. (2006). Low-carbohydrate diets: nutritional and physiological aspects. Obesity Reviews7(1), 49–58.

Center for Disease Control and Prevention: Obesity facts (April 21, 2021).  https://www.cdc.gov/obesity/data/adult.html

Anekwe, C. V., Chandrasekaran, P., & Stanford, F. C. (2020). Ketogenic Diet-induced Elevated Cholesterol, Elevated Liver Enzymes and Potential Non-alcoholic Fatty Liver Disease. Cureus12(1), e6605.

Dashti, H., Al-Zaid, N., Mathew, T., Al-Mousawi, M., Talib, H., Asfar, S., & Behbahani, A. (2006). Long Term Effects of Ketogenic Diet in Obese Subjects with High Cholesterol Level. Molecular and Cellular Biochemistry286(1–2), 1–9.

Drabińska, N., Wiczkowski, W., & Piskuła, M. K. (2021). Recent advances in the application of a ketogenic diet for obesity management. Trends in Food Science & Technology110, 28–38.

Goldberg, I. J., Ibrahim, N., Bredefeld, C., Foo, S., Lim, V., Gutman, D., Huggins, L.-A., & Hegele, R. A. (2021). Ketogenic diets, not for everyone. Journal of Clinical Lipidology15(1), 61–67. https://doi.org/10.1016/j.jacl.2020.10.005

Güzel, O., Yılmaz, U., Uysal, U., & Arslan, N. (2016). The effect of olive oil-based ketogenic diet on serum lipid levels in epileptic children. Neurological Sciences : Official Journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology37(3), 465–470.

Harmon, D., Regner, S., Osman, K., Shahan, C., Kheiri, B., Kadiyala, M., Sokos, G., Sengupta, P. P., Michos, E. D., & Bianco, C. (2020). Dramatic LDL-Cholesterol elevation with Ketogenic Diet: A Case Series. American Journal of Preventive Cardiology3(Supplement).

Hussain, T. A., Mathew, T. C., Dashti, A. A., Asfar, S., Al-Zaid, N., & Dashti, H. M. (2012). Effect of low-calorie versus low-carbohydrate ketogenic diet in type 2 diabetes. Nutrition28(10), 1016–1021.

Salas Noain, J., Minupuri, A., Kulkarni, A., & Zheng, S. (2020). Significant Impact of the Ketogenic Diet on Low-Density Lipoprotein Cholesterol Levels. Cureus12(7), e9418.

Tansey, J. T. (2020). Biochemistry: An integrative approach. Wiley. 

Courtney Simons
Administrator
Courtney Simons is a food science professor. He holds a BS degree in food science and a Ph.D. in cereal science from North Dakota State University.
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