Very-low carbohydrate ketogenic diets can dramatically increase blood cholesterol levels, particularly in normal-weight people, for reasons that are not well understood. This study will enroll normal-weight adults, will identify "responders" who develop high cholesterol on a ketogenic diet, and will measure rates of production and removal of certain types of cholesterol-carrying particles called lipoproteins in responders. The results will clarify the mechanism by which a ketogenic diet can cause high cholesterol in certain susceptible people.

This study will evaluate the mechanism of ketogenic diet-induced hypercholesterolemia in susceptible normal-weight adults. The first stage of screening will identify eligible young adults who are normal-weight and at low cardiovascular risk. The second stage of screening will identify "responders" who demonstrate susceptibility to ketogenic diet-induced hypercholesterolemia by displaying an increase in LDL-cholesterol concentration after a 3-week screening ketogenic diet. Responders will be eligible to complete a randomized crossover clinical study at Washington University School of Medicine in St. Louis, MO. The randomized crossover study will involve isotope tracer studies of lipoprotein and cholesterol kinetics after two separate 4-week dietary interventions [ketogenic diet and control diet], conducted in random order with a 4-week washout period between interventions. All food will be provided to the participants as packed-out meals. Certain outcomes will use data from the screening process, comparing screen successes and screen failures to evaluate factors that could influence susceptibility to ketogenic diet-induced hypercholesterolemia.

Inclusion Criteria:

1. age ≥ 18 and < 40 years
2. BMI ≥ 18.5 and < 25.0 kg/m2
3. baseline serum LDL-c < 150 mg/dL (< 3.9 mmol/L)
4. baseline serum TG < 100 mg/dL (< 1.1 mmol/L)
5. HbA1c ≤ 5.6%.

Exclusion Criteria:

1. personal or family history of familial hypercholesterolemia
2. current use of lipid-lowering drugs
3. currently on a ketogenic diet and unwilling to change diet
4. current tobacco use
5. hypertension
6. prediabetes or diabetes
7. elevated Lp(a) > 6.5% of ApoB-containing lipoproteins at baseline
8. oral contraceptive use
9. contraindication to heparin
10. known atherosclerotic cardiovascular disease
11. unwilling to abstain from alcohol

All raw data used to generate descriptive statistics presented in manuscripts incorporating results generated from this study will be included as supplemental data files as and when required. Fully de-identified raw data, including all outcome measures and tracer enrichments from kinetic studies will be available in .csv format, which can be manipulated by many free and commercial software packages. Individual-level data will be shared as allowed by informed consent agreements approved by the Institutional Review Board (IRB).

Data will be made available upon peer-reviewed publication of the study results or earlier as required by the study sponsor and/or funding sources.

FAIR Data Sharing protocols will be applied so that the data will be Findable, Accessible, Interoperable, and Re-usable.