Low-density lipoprotein cholesterol elevation, ketogenic diets, body mass index, and heterozygous ABCG5 genetic variation: Review, case report, and large population analysis.

BACKGROUND

Low body mass index (BMI) has been associated with marked low-density-lipoprotein-cholesterol (LDL-C) elevations in response to very-low-carbohydrate diets (VLCD).

METHODS

We report a case (51-year-old woman, BMI 18.5 kg/m) whose LDL-C was >500 mg/dL on a VLCD. We characterized her plasma lipoproteins and noncholesterol-sterols (gas chromatography/mass spectrometry) and the DNA sequences of her genes affecting lipid metabolism. We also carried out a large population analysis (224,126 subjects, 54% female, mean age 54 years) examining interrelationships between BMI and serum lathosterol/total cholesterol and β-sitosterol/total cholesterol ratios.

RESULTS

In this case, her LDL-C concentration increased from 142 mg/dL to 555 mg/dL on a VLCD, and her plasma β-sitosterol level was very high at 12.8 mg/L. DNA analysis revealed a heterozygous pathogenic ABCG5 exon 9 variant (c.1323_1324+2del at position g.44051049 TACAC>T). With dietary cholesterol restriction and ezetimibe therapy, her LDL-C and β-sitosterol levels decreased by 75% and 46% to 139 mg/dL and 7.1 mg/L, respectively. In the population analysis, we noted a significant inverse correlation between BMI and the plasma β-sitosterol/total cholesterol ratio (r = -0.573, P < .00001). Those with a BMI <20 kg/m had mean β-sitosterol/total cholesterol values that were significantly higher (+63%, P < .00001) than values in obese women. The converse was true for the plasma lathosterol/total cholesterol ratio. Similar findings were noted in men.

CONCLUSIONS

Our data are consistent with the concepts that low BMI predisposes to increased plasma β-sitosterol/total cholesterol ratios and an increased serum LDL-C when on high cholesterol VLCD, and that this response may be markedly enhanced in subjects with pathogenic heterozygous ABCG5 variants.

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