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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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 2

Altered plasma bile acid composition in heterozygous carriers of CYP8B1 mutations.

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Altered plasma bile acid composition in heterozygous carriers of CYP8B1 ...
CYP8B1 is a 12α-hydroxylase, catalyzing the conversion of 7α-hydroxy-4-cholesten-3-one to generate 7α,12α-dihydroxy-4-cholesten-3-one. (A) Schematic of the bile acid synthesis pathway with CYP8B1 indicated. (B) The ratio of CYP8B1 product (7α,12α-dihydroxy-4-cholesten-3-one) to substrate (7α-hydroxy-4-cholesten-3-one) is decreased in mutation carriers. In addition, the ratios of (C) 12α to non-12α bile acids, and (D) cholic acid (CA) to chenodeoxycholic acid (CDCA) are decreased in CYP8B1 mutation carriers. (E) The composition of the plasma bile acid pool is shown in carriers and noncarriers. In italic font are the bile acids significantly different between mutation carriers and controls (also shown in Supplemental Table 2). Data (nonparametric) are shown as box-and-whisker plots with median (horizontal lines), interquartile range (boxes), and whiskers generated by Tukey’s method, and were analyzed using the Mann-Whitney U test.