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Randomized Controlled Trial
. 2025 Feb 8;17(4):619.
doi: 10.3390/nu17040619.

Cholesin mRNA Expression in Human Intestinal, Liver, and Adipose Tissues

Hannah Gilliam-Vigh  1   2 , Malte P Suppli  1 , Sebastian M N Heimbürger  1 , Asger B Lund  1   3   4 , Filip K Knop  1   4 , Anne-Marie Ellegaard  1
Affiliations
Randomized Controlled Trial

Cholesin mRNA Expression in Human Intestinal, Liver, and Adipose Tissues

Hannah Gilliam-Vigh et al. Nutrients. .

Abstract

Objective: Cholesin is a recently discovered gut-derived hormone secreted by enterocytes upon dietary cholesterol uptake via the transmembrane sterol transporter Niemann-Pick disease C1-like intracellular cholesterol transporter 1 (NPC1L1). In the liver, cholesin activates G protein-coupled receptor 146 (GPR146), causing reduced cholesterol synthesis. In this exploratory, hypothesis-generating study based on post hoc analysis, human data on the cholesin system are presented.

Methods: Mucosal biopsies were collected throughout the intestinal tract from 12 individuals with type 2 diabetes (T2D) and 12 healthy, matched controls. Upper small intestinal mucosal biopsies were collected from 20 individuals before and after Roux-en-Y gastric bypass (RYGB) surgery. Liver biopsies were collected from 12 men with obesity and 15 matched controls without obesity. Subcutaneous abdominal adipose tissue biopsies were collected from 20 men with type 1 diabetes (T1D). All biopsies underwent full mRNA sequencing.

Results: Cholesin mRNA expression was observed throughout the intestinal tracts of the individuals with T2D and the controls, in the livers of men with and without obesity, and in adipose tissue of men with T1D. NPC1L1 mRNA expression was robust throughout the small intestines but negligible in the large intestines of both individuals with and without T2D. RYGB surgery induced the expression of NPC1L1 mRNA in the upper small intestine. GPR146 mRNA was expressed in the livers of men, both with and without obesity, and in the adipose tissue of men with T1D, but not in the intestines.

Conclusions: Our results suggest a role of the cholesin system in human physiology, but whether it is perturbed in metabolic diseases remains unknown.

Clinical trial registration numbers: NCT03044860, NCT03093298, NCT02337660, NCT03734718.

Keywords: cholesin; cholesterol; intestines; liver; mRNA; white adipose tissue.

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Conflict of interest statement

H.G.-V. has received unrestricted research funds from Zealand A/S; M.P.S. has received travel compensation from Novo Nordisk Denmark A/S and Bayer A/S and is a co-founder of Medvægt ApS; S.M.N.H. has received unrestricted grants from The Leona M. and Harry B. Helmsley Charitable Trust and Aase og Ejnar Danielsens Fond; A.B.L. has served on scientific advisory panels and/or received honoraria or research support from Boehringer Ingelheim, Eli Lilly, Novo Nordisk, and Zealand Pharma; F.K.K. has served on scientific advisory panels and/or been part of speaker’s bureaus for, served as a consultant to, holds stocks in, and/or received research support from 89bio, Amgen, Altimmune, AstraZeneca, Bayer, Boehringer Ingelheim, Carmot Therapeutics, Chr. Hansen, Cytoki Pharma, Eli Lilly, Gubra, MedImmune, MSD/Merck, Mundipharma, Norgine, Novo Nordisk, MedImmune, Pharmacosmos, Sanofi, Structure Therapeutics, Zealand Pharma, and Zucara, is a co-founder of and minority shareholder in Antag Therapeutics, and is currently employed full-time by Novo Nordisk. A.-M.E. declares no conflicts of interest. The authors declare that this study received funding from Sanofi Aventis. The funder was not involved in the study design, collection, analysis, interpretation of data, the writing of this article or the decision to submit it for publication.

Figures

Figure 1
Figure 1
mRNA expression levels of NPC1L1 in the intestine, in the intestine before and after RYGB, in the liver, and in adipose tissue. mRNA expressions of NPC1L1 in mucosal biopsies sampled throughout the small intestine (white background/light blue background (light blue indicates sections of the intestine where the exact locations of the biopsies were taken with considerable uncertainty)) and the large intestine (grey background) in 12 individuals with type 2 diabetes (blue) and in 12 age- and body-mass-index-matched healthy controls (grey) (A); in small intestinal mucosal samples from 19 individuals collected after RYGB in the alimentary limb (yellow), biliopancreatic limb (orange), common channel (red), and before RYGB (grey) (B); in transcutaneously sampled liver biopsies from 12 men with obesity (green) and 15 lean controls (grey) (C); in subcutaneous adipose tissue biopsies from 20 men with type 1 diabetes (grey) (D). Dots are individual data points; boxes represent inter-quartile ranges, and whiskers extend from the 25th percentile to the smallest value within 1.5 times the interquartile range below it and from the 75th percentile to the largest value within 1.5 times the interquartile range above it (encompassing data points not deemed outliers). Statistical significance is represented as follows: ** for p < 0.01, * for p < 0.05. For non-significant results (p ≥ 0.05), the p values are not displayed. Abbreviations: Asc., ascending; Desc., descending; NPC1L1, Niemann–Pick disease C1-like intracellular cholesterol transporter 1; Post AL, postsurgery alimentary limb; Post BL, postsurgery biliopancreatic limb; Post CC, postsurgery common channel; Pre, presurgery; RPKM, reads per kilobase of transcript per million mapped reads; Trans., transverse.
Figure 2
Figure 2
mRNA expression levels of cholesin in the intestine, in the intestine before and after RYGB, in the liver, and in the adipose tissue. mRNA expression of cholesin in mucosal biopsies sampled throughout the small intestine (white background/light blue background (light blue indicates sections of the intestine where the exact locations of the biopsies were taken with considerable uncertainty)) and the large intestine (grey background) in 12 individuals with type 2 diabetes (blue) and in 12 age- and body-mass-index-matched healthy controls (grey) (A); in small intestinal mucosal samples from 19 individuals collected after RYGB in the alimentary limb (yellow), biliopancreatic limb (orange), common channel (red), and before RYGB (grey) (B); in transcutaneously sampled liver biopsies from 12 men with obesity (green) and 15 lean controls (grey) (C); in subcutaneous adipose tissue biopsies from 20 men with type 1 diabetes (grey) (D). Dots are individual data points; boxes represent inter-quartile ranges, and whiskers extend from the 25th percentile to the smallest value within 1.5 times the interquartile range below it and from the 75th percentile to the largest value within 1.5 times the interquartile range above it (encompassing data points not deemed outliers). Abbreviations: Asc., ascending; Desc., descending; Post AL, postsurgery alimentary limb; Post BL, postsurgery biliopancreatic limb; Post CC, postsurgery common channel; Pre, presurgery; RPKM, reads per kilobase of transcript per million mapped reads; Trans., transverse.
Figure 3
Figure 3
mRNA expression levels of GPR146 in the intestine, in the intestine before and after RYGB, in the liver, and in the adipose tissue. mRNA expression of GPR146 in mucosal biopsies sampled throughout the small intestine (white background/light blue background (light blue indicates sections of the intestine where the exact locations of the biopsies were taken with considerable uncertainty)) and the large intestine (grey background) in 12 individuals with type 2 diabetes (blue) and in 12 age- and body-mass-index-matched healthy controls (grey) (A); in small intestinal mucosal samples from 19 individuals collected after RYGB in the alimentary limb (yellow), biliopancreatic limb (orange), common channel (red), and before RYGB (grey) (B); in transcutaneous liver biopsies from 12 men with obesity (green) and 15 lean controls (grey) (C); in subcutaneously sampled adipose tissue biopsies from 20 men with type 1 diabetes (grey) (D). Dots are individual data points; boxes represent inter-quartile ranges, and whiskers extend from the 25th percentile to the smallest value within 1.5 times the interquartile range below it and from the 75th percentile to the largest value within 1.5 times the interquartile range above it (encompassing data points not deemed outliers). Abbreviations: Asc., ascending; Desc., descending; GPR146, G protein-coupled receptor 146; Post AL, postsurgery alimentary limb; Post BL, postsurgery biliopancreatic limb; Post CC, postsurgery common channel; Pre, presurgery; RPKM, reads per kilobase of transcript per million mapped reads; Trans., transverse.
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