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ARS Home » Plains Area » Houston, Texas » Children's Nutrition Research Center » Research » Publications at this Location » Publication #400176
Research Project: Metabolic and Epigenetic Regulation of Nutritional Metabolism

Location: Children's Nutrition Research Center

Title: Haploinsufficiency of CYP8B1 associates with increased insulin sensitivity in humans

Author
item ZHONG, SHIQI - National University Of Singapore
item CHEVRE, RAPHAEL - Singapore Immunology Network (SIGN), Agency For Science, Technology And Research
item CASTANO MAYAN, DAVID - National University Of Singapore
item CORLIANO, MARIA - National University Of Singapore
item COCHRAN, BLAKE - University Of New South Wales
item PING SEM, KAI - Singapore Immunology Network (SIGN), Agency For Science, Technology And Research
item VAN DIJIK, THEO - University Of Groningen
item PENG, JIANHE - Singapore Immunology Network (SIGN), Agency For Science, Technology And Research
item JUIN TAN, LIANG - Singapore Immunology Network (SIGN), Agency For Science, Technology And Research
item HARTIMATH, SIDDESH - Singapore Immunology Network (SIGN), Agency For Science, Technology And Research
item RAMASAMY, BOOMINATHAN - Singapore Immunology Network (SIGN), Agency For Science, Technology And Research
item CHENG, PETER - Singapore Immunology Network (SIGN), Agency For Science, Technology And Research
item GROEN, ALBERT - University Of Groningen
item KUIPERS, FOLKERT - University Of Groningen
item GOGGI, JULIAN - Singapore Immunology Network (SIGN), Agency For Science, Technology And Research
item DRUM, CHESTER - National University Of Singapore
item VAN DAM, ROB - National University Of Singapore
item SAN TAN, RU - National Heart Centre Singapore
item RYE, KERRY-ANNE - University Of New South Wales
item HAYDEN, MICHAEL - University Of British Columbia
item CHENG, CHING-YU - Singapore National Eye Centre
item CHACKO, SHAJI - Children'S Nutrition Research Center (CNRC)
item FLANNICK, JASON - Broad Institute Of Mit/harvard
item SIM, XUELING - National University Of Singapore
item CHANG TAN, HONG - Singapore General Hospital
item SINGARAJA, ROSHNI - National University Of Singapore

Submitted to: Journal of Clinical Investigation
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/8/2022
Publication Date: 11/1/2022
Citation: Zhong, S., Chevre, R., Castano Mayan, D., Corliano, M., Cochran, B.J., Ping Sem, K., Van Dijik, T.H., Peng, J., Juin Tan, L., Hartimath, S.V., Ramasamy, B., Cheng, P., Groen, A.K., Kuipers, F., Goggi, J.L., Drum, C., Van Dam, R.M., San Tan, R., Rye, K., Hayden, M.R., Cheng, C., Chacko, S., Flannick, J., Sim, X., Chang Tan, H., Singaraja, R.R. 2022. Haploinsufficiency of CYP8B1 associates with increased insulin sensitivity in humans. Journal of Clinical Investigation. 132(21). Article e152961. https://doi.org/10.1172/JCI152961.
DOI: https://doi.org/10.1172/JCI152961

Interpretive Summary: Bile acids are steroid acids that are synthesized in the liver. There is substantial data linking bile acids to obesity and diabetes risk. Insulin resistance is a condition when cells in muscles, fat, and liver do not respond efficiently to insulin and are unable to easily take up glucose from circulation. Insulin resistance condition has been shown to be associated with increased concentration of certain hydroxylated bile acids. Scientists in Houston, Texas showed that decreased concentration of certain hydroxylated bile acids and concomitant increase in non-hydroxylated bile acids because of some genetic mutations in humans increased insulin sensitivity. This finding proposes a novel target for future therapeutic intervention for diabetes.

Technical Abstract: Cytochrome P450 family 8 subfamily B member 1 (CYP8B1) generates 12a-hydroxylated bile acids (BAs) that are associated with insulin resistance in humans. 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. Mutation carriers had lower plasma 12a-hydroxylated/non–12a-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. Our findings suggest that increased circulatory CDCA due to reduced CYP8B1 activity increases skeletal muscle insulin sensitivity, contributing to increased whole-body insulin sensitization.