Upregulation of hepatic bile acid synthesis via fibroblast growth factor 19 is defective in gallstone disease but functional in overweight individuals

Abstract

Background: Fibroblast growth factor 19 (FGF19) is an enteric hormone regulating bile acid de novo synthesis by sensing ileal bile acid flux. However, the role of FGF19 in cholelithiasis has not yet been elucidated and therefore is investigated in the present study. Methods: Total mRNA and protein were isolated from ileal biopsies and used for tissue expression analysis. FGF19, 7a-hydroxycholesterol (7a-OH-Chol), 27-hydroxycholesterol (27-OH-Chol), and different bile acids were determined in the blood samples. Results: FGF19 serum levels did not differ between gallstone carriers and controls but were significantly decreased in the overweight individuals (À32%, p ¼ 0.0002), irrespective of gallstone status (normalweight to overweight controls À29%, p ¼ 0.0017; normalweight to overweight gallstone carriers À44%, p ¼ 0.0338), and correlated inversely with bodyweight (p < 0.0001, r ¼ À0.3317). Compared to non-overweight controls, apical sodium-dependent bile acid transporter expression was significantly diminished in the non-overweight gallstone carriers (À42%, P mRNA ¼ 0.0393; À52%, p protein ¼ 0.0169) as well as in the overweight controls (À24%, P mRNA ¼ 0.0148; À43%, p protein ¼ 0.0017). FGF19 expression varied widely and was similar in all groups. A significant negative correlation was noted between 7a-OH-Chol, 27-OH-Chol, and FGF19 serum levels (p < 0.01; r 7a-OH-Chol ¼ À0.2155; r 27-OH-Chol ¼ À0.2144) in obesity. Conclusion: Upregulation of hepatic bile acid synthesis via FGF 19 is defective in gallstone disease but functional in overweight individuals.

Mechanisms of enterohepatic fibroblast growth factor 15/19 signaling in health and disease

“…This is supported by genotyping studies that revealed enrichment of a KLB (encoding b-Klotho) risk allele in gallstone carriers [69]. The potential local mode of action of gallbladder-derived FGF19 proposed by Zweers et al [67], would moreover be in line with the recent finding that neither serum levels of FGF19 nor its intestinal expression are altered in gallstone patients devoid of ileal inflammation [70].…”

Targeting bile acid metabolism in obesity reduction: A systematic review and meta‐analysis

“…Three cross‐sectional studies 15–17 were graded as unsatisfactory after risk of bias assessment using NOS. Five other studies were also considered to be at high risk of bias due to other reasons not specifically given in the risk of bias assessment, including lack of control for confounding, 15 high variation of BMI in the lean group, 18 insufficient information, 19,20 and only selecting participants with a good response to surgery for BA measurement 21 …”

Acute caloric restriction counteracts hepatic bile acid and cholesterol deficiency in morbid obesity

“…The synthesis of BAs and the synthesis of cholesterol both correlate with body mass index (BMI) , and studies using different techniques have established that they are both considerably increased in morbid obesity , as is the clearance of LDL from blood, despite the fact that the hepatic synthesis of the LDL precursor very low‐density lipoprotein is increased . Importantly, it has long been established that the faecal excretion of cholesterol and particularly of BAs is increased in morbid obesity by ~1.5‐fold .…”