Suppressed Hepatic Bile Acid Signaling Despite Elevated Production of Primary and Secondary Bile Acids in NAFLD

Jiao, Na; Baker, Susan S.; Chapa-Rodríguez, Adrián; Liu, Wensheng; Nugent, Colleen A.; Tsompana, Maria; Mastrandrea, Lucy D.; Buck, Michael A.; Baker, Robert D.; Genco, Robert J.; Zhu, Rong; Zhu, Lixin

doi:10.1016/s0016-5085(17)33607-7

Cited by 16 publications

(12 citation statements)

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“…The changes in BAs were more likely to be linked with PFAS exposure than NAFLD per se, as we did not observe any significant increases in hepatic BAs in NAFLD, except for weak associations (elevated LCA, downregulated TMCA) in female subjects. While elevated levels of BAs in NAFLD have been reported [46], some of the results may be linked with obesity rather than NAFLD/NASH due to a significant difference in the BMI of controls versus NAFLD subjects in many studies [45] and as elevated BA concentrations have been reported in obese subjects without NAFLD [47]. In our study, all subjects, including those with normal liver fat, were obese (BMI>30), thus allowing us to control for the effect of BMI.…”

Section: J O U R N a L P R E -P R O O Fmentioning

confidence: 77%

Exposure to environmental contaminants is associated with altered hepatic lipid metabolism in non-alcoholic fatty liver disease

Sen

Qadri

Luukkonen

et al. 2022

Journal of Hepatology

153

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Section: J O U R N a L P R E -P R O O Fmentioning

confidence: 77%

Exposure to environmental contaminants is associated with altered hepatic lipid metabolism in non-alcoholic fatty liver disease

Sen

Qadri

Luukkonen

et al. 2022

Journal of Hepatology

153

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“…[4] Gut microbiota initiate primary bile acid metabolism by deconjugating GCA and GCDCA back to CA and CDCA, a critical step catalyzed by choloylglycine hydrolase, also known as bile salt hydrolase (BSH). Although some studies have not demonstrated altered serum bile acid concentrations in patients with NASH [5], other studies have shown that elevated bile acid concentrations are associated with the J o u r n a l P r e -p r o o f presence and severity of NAFLD [6,7], and that DCA concentrations are specifically elevated in patients with NASH relative to healthy adults. [6,8] Given the link between bile acids and metabolic regulation, there is growing interest in understanding how bile acid dysregulation may contribute to NASH pathogenesis and progression.…”

Section: Figures and Tablesmentioning

confidence: 99%

Pegbelfermin selectively reduces secondary bile acid concentrations in patients with non-alcoholic steatohepatitis

et al. 2022

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Background & Aims Increased serum bile acids (BAs) have been observed in patients with non-alcoholic steatohepatitis (NASH). Pegbelfermin (PGBF), a polyethylene glycol-modified (PEGylated) analogue of human fibroblast growth factor 21 (FGF21), significantly decreased hepatic steatosis and improved fibrosis biomarkers and metabolic parameters in patients with NASH in a phase IIa trial. This exploratory analysis evaluated the effect of PGBF on serum BAs and explored potential underlying mechanisms. Methods Serum BAs and 7α-hydroxy-4-cholesten-3-one (C4) were measured by HPLC-mass spectrometry (MS) using serum collected in studies of patients with NASH ( NCT02413372 ) and in overweight/obese adults ( NCT03198182 ) who received PGBF. Stool samples were collected in NCT03198182 to evaluate faecal BAs by liquid chromatography (LC)-MS and the faecal microbiome by metagenetic and metatranscriptomic analyses. Results Significant reductions from baseline in serum concentrations of the secondary BA, deoxycholic acid (DCA), and conjugates, were observed with PGBF, but not placebo, in patients with NASH; primary BA concentrations did not significantly change in any arm. Similar effects of PGBF on BAs were observed in overweight/obese adults, allowing for an evaluation of the effects of PGBF on the faecal microbiome and BAs. Faecal transcriptomic analysis showed that the relative abundance of the gene encoding choloylglycine hydrolase, a critical enzyme for secondary BA synthesis, was reduced after PGBF, but not placebo, administration. Furthermore, a trend of reduction in faecal secondary BAs was observed. Conclusions PGBF selectively reduced serum concentrations of DCA and conjugates in patients with NASH and in healthy overweight/obese adults. Reduced choloylglycine hydrolase gene expression and decreased faecal secondary BA levels suggest a potential role for PGBF in modulating secondary BA synthesis by gut microbiome. The clinical significance of DCA reduction post-PGBF treatment warrants further investigation. Lay summary Pegbelfermin (PGBF) is a hormone that is currently being studied in clinical trials for the treatment of non-alcoholic fatty liver disease. In this study, we show that PGBF treatment can reduce bile acids that have previously been shown to have toxic effects on the liver. Additional studies to understand how PGBF regulates bile acids may provide additional information about its potential use as a treatment for fatty liver.

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“…Gut microbiome is a stool-based non-invasive biomarker for metabolic diseases and cancers 5 , 6 . Many studies have reported that the gut microbiome is an important etiological element in the initiation and progression of CRC 4 , 7 and have identified some fecal microbial markers of CRC 8 – 10 .…”

Section: Introductionmentioning

confidence: 99%

Identification of microbial markers across populations in early detection of colorectal cancer

et al. 2021

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Associations between gut microbiota and colorectal cancer (CRC) have been widely investigated. However, the replicable markers for early-stage adenoma diagnosis across multiple populations remain elusive. Here, we perform an integrated analysis on 1056 public fecal samples, to identify adenoma-associated microbial markers for early detection of CRC. After adjusting for potential confounders, Random Forest classifiers are constructed with 11 markers to discriminate adenoma from control (area under the ROC curve (AUC) = 0.80), and 26 markers to discriminate adenoma from CRC (AUC = 0.89), respectively. Moreover, we validate the classifiers in two independent cohorts achieving AUCs of 0.78 and 0.84, respectively. Functional analysis reveals that the altered microbiome is characterized with increased ADP-l-glycero-beta-d-manno-heptose biosynthesis in adenoma and elevated menaquinone-10 biosynthesis in CRC. These findings are validated in a newly-collected cohort of 43 samples using quantitative real-time PCR. This work proves the validity of adenoma-specific markers across multi-populations, which would contribute to the early diagnosis and treatment of CRC.

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Suppressed Hepatic Bile Acid Signaling Despite Elevated Production of Primary and Secondary Bile Acids in NAFLD

Cited by 16 publications

References 0 publications

Exposure to environmental contaminants is associated with altered hepatic lipid metabolism in non-alcoholic fatty liver disease

Exposure to environmental contaminants is associated with altered hepatic lipid metabolism in non-alcoholic fatty liver disease

Pegbelfermin selectively reduces secondary bile acid concentrations in patients with non-alcoholic steatohepatitis

Identification of microbial markers across populations in early detection of colorectal cancer

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