Haploinsufficiency of CYP8B1 associates with increased insulin sensitivity in humans
Shiqi Zhong, … , Hong Chang Tan, Roshni R. Singaraja
Shiqi Zhong, … , Hong Chang Tan, Roshni R. Singaraja
Published September 15, 2022
Citation Information: J Clin Invest. 2022;132(21):e152961. https://doi.org/10.1172/JCI152961.
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Clinical Medicine Endocrinology

Haploinsufficiency of CYP8B1 associates with increased insulin sensitivity in humans

Abstract

BACKGROUND Cytochrome P450 family 8 subfamily B member 1 (CYP8B1) generates 12α-hydroxylated bile acids (BAs) that are associated with insulin resistance in humans.METHODS To determine whether reduced CYP8B1 activity improves insulin sensitivity, we sequenced CYP8B1 in individuals without diabetes and identified carriers of complete loss-of-function (CLOF) mutations utilizing functional assays.RESULTS Mutation carriers had lower plasma 12α-hydroxylated/non–12α-hydroxylated BA and cholic acid (CA)/chenodeoxycholic acid (CDCA) ratios compared with age-, sex-, and BMI-matched controls. During insulin clamps, hepatic glucose production was suppressed to a similar magnitude by insulin, but glucose infusion rates to maintain euglycemia were higher in mutation carriers, indicating increased peripheral insulin sensitivity. Consistently, a polymorphic CLOF CYP8B1 mutation associated with lower fasting insulin in the AMP-T2D-GENES study. Exposure of primary human muscle cells to mutation-carrier CA/CDCA ratios demonstrated increased FOXO1 activity, and upregulation of both insulin signaling and glucose uptake, which were mediated by increased CDCA. Inhibition of FOXO1 attenuated the CDCA-mediated increase in muscle insulin signaling and glucose uptake. We found that reduced CYP8B1 activity associates with increased insulin sensitivity in humans.CONCLUSION Our findings suggest that increased circulatory CDCA due to reduced CYP8B1 activity increases skeletal muscle insulin sensitivity, contributing to increased whole-body insulin sensitization.FUNDING Biomedical Research Council/National Medical Research Council of Singapore.

Authors

Shiqi Zhong, Raphael Chèvre, David Castaño Mayan, Maria Corlianò, Blake J. Cochran, Kai Ping Sem, Theo H. van Dijk, Jianhe Peng, Liang Juin Tan, Siddesh V. Hartimath, Boominathan Ramasamy, Peter Cheng, Albert K. Groen, Folkert Kuipers, Julian L. Goggi, Chester Drum, Rob M. van Dam, Ru San Tan, Kerry-Anne Rye, Michael R. Hayden, Ching-Yu Cheng, Shaji Chacko, Jason Flannick, Xueling Sim, Hong Chang Tan, Roshni R. Singaraja

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Figure 1

Identification of loss-of-function mutations in CYP8B1.

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Identification of loss-of-function mutations in CYP8B1. CYP8B1 was Sange...
CYP8B1 was Sanger sequenced in 8112 individuals and 100 nonsynonymous variants, frameshifts, and insertions/deletions in the coding region were identified. Each variant was generated by site-directed mutagenesis in human CYP8B1 cDNA; in vitro assays were performed to quantify the CYP8B1 product 7α,12α-dihydroxy-4-cholesten-3-one for each variant, which was then graphed as a percentage of the substrate generated by wild-type CYP8B1. Twenty-three complete loss-of-function mutations in CYP8B1 were identified. n = 3–6 per variant, with each n performed in triplicate. Data are mean ± SEM. See complete unedited blots in the supplemental material.