The DOI matches its Crossref record; 49 of the 50 references it cites were found in a registry or an index.
Suppressed hepatic bile acid signalling despite elevated production of primary and secondary bile acids in NAFLD
Abstract
OBJECTIVE: Bile acids are regulators of lipid and glucose metabolism, and modulate inflammation in the liver and other tissues. Primary bile acids such as cholic acid and chenodeoxycholic acid (CDCA) are produced in the liver, and converted into secondary bile acids such as deoxycholic acid (DCA) and lithocholic acid by gut microbiota. Here we investigated the possible roles of bile acids in non-alcoholic fatty liver disease (NAFLD) pathogenesis and the impact of the gut microbiome on bile acid signalling in NAFLD. DESIGN: Serum bile acid levels and fibroblast growth factor 19 (FGF19), liver gene expression profiles and gut microbiome compositions were determined in patients with NAFLD, high-fat diet-fed rats and their controls. RESULTS: -taurocholate cotransporting polypeptide and paraoxonase 1, no change in mRNA expression for small heterodimer partner and bile salt export pump, and reduced serum FGF19 were evidence of impaired FXR and fibroblast growth factor receptor 4 (FGFR4)-mediated signalling in NAFLD. Taurine and glycine metabolising bacteria were increased in the gut of patients with NAFLD, reflecting increased secondary bile acid production. Similar changes in liver gene expression and the gut microbiome were observed in high-fat diet-fed rats. CONCLUSIONS: The serum bile acid profile, the hepatic gene expression pattern and the gut microbiome composition consistently support an elevated bile acid production in NAFLD. The increased proportion of FXR antagonistic bile acid explains, at least in part, the suppression of hepatic FXR-mediated and FGFR4-mediated signalling. Our study suggests that future NAFLD intervention may target the components of FXR signalling, including the bile acid converting gut microbiome.
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“Jiao et al. (2018) found that MAFLD patients present elevated primary and secondary bile acids, among which the proportion of DCA is increased and CDCA is decreased.”
From Akkermansia muciniphila alleviates high‐fat‐diet ‐related metabolic‐associated fatty liver disease by modulating gut microbiota and bile acids (2023) · cites this paper as Jiao et al. (2018)
In the citing paper
“Additionally, hepatic CYP7A1 expression is enhanced.”
From Akkermansia muciniphila alleviates high‐fat‐diet ‐related metabolic‐associated fatty liver disease by modulating gut microbiota and bile acids (2023) · cites this paper as Jiao et al. (2018)
In the citing paper
“With increasing severity of NASH and fibrosis, BA levels tend to increase and the composition of BAs changes”
From Novel therapeutic targets for cholestatic and fatty liver disease (2022) · cites this paper as [91]
In the citing paper
“First, the gut microbiota may affect gastrointestinal transit through its regulation of BA synthesis. The gut microbiota is equipped with enzymes for the production of secondary BAs, which may suppress the FGF19- and FXR-mediated signaling, leading to the induction of CYP7A1 [ 49 , 50 ], and consequently elevated de novo BA synthesis and improved colonic transit.”
From Role of gut microbiota in functional constipation (2021) · cites this paper as [49]
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“Patients with NASH and NAFLD had increased serum and fecal BA levels (37-39).”
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“…X receptor (FXR) is a bile acid (BA) receptor activated by specific BA metabolites, When FXR is activated, it inhibits the production of bile acids, inhibits the production of lipids, decreases triglycerides, and lowers blood glucose (Jiao et al., 2017; Sun et al., 2021; Xiang et al., 2021).”
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“Secondary bile acids are produced by bacteria in the gut through modification of endogenously produced primary bile acids [89].”
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“The levels of both primary and secondary BAs are observed to increase in NAFLD patients (Jiao et al., 2018).”
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“[107] Nevertheless, the same study revealed that deoxycholic acid (DCA), an FXR antagonist, was increased, whereas chenodeoxycholic acid, an FXR agonist, was decreased in MASLD, suggesting that FXR signaling is inhibited in MASLD, which could promote obesity and steatosis in the liver (Figure 2D).”
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“mRNA expression of CYP7A1, the rate-limiting enzyme in bile acid synthesis, was induced in human NASH livers (49).”
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The Role of Intestinal C‐type Regenerating Islet Derived‐3 Lectins for Nonalcoholic Steatohepatitis
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“Both alcoholic liver disease and NASH are dysbiosis-driven diseases and can be transmitted by microbiota transfer.((2,39,40)) It is likely that functional microbiota changes associated with dysbiosis, such as ethanol production, choline metabolism, and trimethylamine synthesis, and changes in bile acids are more impor…”
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“(10) reported that the serum BA profile in NASH patients was characterized by an elevated ratio of secondary to primary BAs and decreased CDCAs.”
BackgroundJi, X., Zhu, L., Chang, K., Zhang, R., Chen, Y., Yin, H., Jin, J., & Zhao, L. (2021) · Carbohydrate Polymers · doi:10.1016/j.carbpol.2021.118716 · Cited by 45
Self-citationLean nonalcoholic fatty liver disease and sarcopenia
Chen, M., Cao, Y. Y., Ji, G., & Zhang, L. (2023) · Frontiers in Endocrinology · doi:10.3389/fendo.2023.1217249 · Cited by 47
“The gut microbiomes affect FXR-mediated signaling pathways in the liver and gut by interacting with BAs, which is associated with the pathogenesis of lean NAFLD (150, 151).”
BackgroundMAFLD: an optimal framework for understanding liver cancer phenotypes
Crane, H., Gofton, C., Sharma, A., & George, J. (2023) · Journal of Gastroenterology · doi:10.1007/s00535-023-02021-7 · Cited by 46
The Potential of Bile Acids as Biomarkers for Metabolic Disorders
Yin, C., Zhong, R., Zhang, W., Liu, L., Chen, L., & Zhang, H. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241512123 · Cited by 45
MASLD development: From molecular pathogenesis toward therapeutic strategies
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“(2) NAFLD is closely associated with metabolic comorbidities, including obesity and diabetes; subsequently, the incidence of NAFLD, NASH, liver fibrosis, and Abbreviations: ALT, alanine aminotransferase; AOR, adjusted odds ratio; AST, aspartate aminotransferase; CA, cholic acid; CAP, controlled attenuation parameter;…”
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“In NAFLD, their number is increased and they contribute to the suppression of hepatic FXR-mediated metabolic signaling, which further promotes IR [28].”
BackgroundYu, J., Zhang, H., Chen, L., Ruan, Y., Chen, Y., & Liu, Q. (2021) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2021.698852 · Cited by 45
“…E. cloacae), with the capacity to Frontiers in Cellular and Infection Microbiology | www.frontiersin.org 8 produce endotoxins, may increase hepatic injury by inducing macrophage activation via the LPS-Toll-like receptor 4 (TLR4) pathway (Kapil et al., 2016; Carpino et al., 2020; Fei et al., 2020).”
BackgroundHernandez, G. V., Smith, V. A., Melnyk, M., Burd, M. A., Sprayberry, K. A., Edwards, M. S., Peterson, D. G., Bennet, D. C., Fanter, R. K., Columbus, D. A., et al. (2020) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00344.2019 · Cited by 44
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The role of microbiota in nonalcoholic fatty liver disease
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Bavachinin inhibits cholesterol synthesis enzyme FDFT1 expression via AKT/mTOR/SREBP-2 pathway
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“Although BA levels are increased in patients with NAFLD, FXR-mediated signaling is inhibited, and the concentration of circulating FGF19 is decreased (Jiao et al., 2018; Nobili et al., 2018).”
BackgroundHuang, Y., Chen, H., Chen, J., Wu, Q.-X., Zhang, W., Li, D., Lu, Y., & Chen, Y. (2024) · Phytomedicine · doi:10.1016/j.phymed.2024.155919 · Cited by 43
The physiology of MASLD: molecular pathways between liver and adipose tissues
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“Suppressed FXR transcriptional signaling has been found in MASLD [90].”
The Liver under the Spotlight: Bile Acids and Oxysterols as Pivotal Actors Controlling Metabolism
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“Indeed, in a recent study, Raselli and colleagues measured in liver samples, an increased level of 24(S)-OHC and 7-OHC derivatives in NASH patients compared to controls [122].”
BackgroundInfluentialEffects of Oral Glucose-Lowering Agents on Gut Microbiota and Microbial Metabolites
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“In subjects with diabetes and metabolic diseases, BAs’ pool composition altered (60).”
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“…expenditure and a chronic inflammatory state [10], while elevated production of deoxycholic acid in NASH patients, attributed to the enrichment abundance of bacteria producing secondary bile acids, inhibited FXR signalling, impeding lipid and glucose metabolism in the liver and intestine [11].”
BackgroundPetrov, P., García‐Mediavilla, M. V., Guzmán, C., Porras, D., Nistal, E., Martínez‐Flórez, S., Castell, J. V., González‐Gallego, J., Sánchez‐Campos, S., & Jover, R. (2019) · Molecular Nutrition & Food Research · doi:10.1002/mnfr.201900487 · Cited by 42
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“92 However, CYP7A1 mRNA levels decline with the progression of MASH-associated liver fibrosis.”
BackgroundGut Microbiota at the Crossroad of Hepatic Oxidative Stress and MASLD
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“Moreover, the gut microbiota can participate in BA conversion metabolism, with bacteria encoding bile salt hydrolase (BSH), 7-alpha hydroxysteroid dehydrogenase (7-alpha HSDH), and 7-alpha-dehydroxylase playing key roles [43–45].”
Role of Gut Microbial Metabolites in Cardiovascular Diseases—Current Insights and the Road Ahead
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“IPA augments ATP-binding cassette Primary BAs can activate FXR to a greater extent relative to secondary BAs [231]. class A1 (ABCA1) and enhances macrophage mediated reverse cholesterol FXR downregulates BA uptake into the hepatocytes and augments the expression of ATP-binding casse(cid:308)e…”
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Gut Microbiota and Metabolic Dysfunction-Associated Steatotic Liver Disease
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“In contrast, Jiao and colleagues [39] found increased DCA and decreased CDCA levels in NAFLD patients.”
BackgroundKaminsky-Kolesnikov, Y., Rauchbach, E., Abu-Halaka, D., Hahn, M., García-Ruiz, C., Fernandez-Checa, J. C., Madar, Z., & Tirosh, O. (2020) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2020/5393761 · Cited by 39
“Recent studies reported that around 50% of all NAFLD cases may progress to HCC without fibrosis [29, 30].”
BackgroundInfluential
Metadata
- Authors
- Jiao, N., Baker, S. S., Chapa-Rodriguez, A., Liu, W., Nugent, C. A., Tsompana, M., Mastrandrea, L., Buck, M. J., Baker, R. D., Genco, R. J., Zhu, R., & Zhu, L.
- Affiliations
- Tongji University (CN)
- University at Buffalo, State University of New York (US)
- Department of Pediatrics, Digestive Diseases and Nutrition Center, The State University of New York at Buffalo, Buffalo, New York, USA
- Corresponding author
- Baker, Susan S
- Zhu, Lixin
- ORCID
- Venue
- Gut
- Publisher
- BMJ
- Published
- 2017-08-03
- Volume
- 67
- Issue
- 10
- Pages
- 1881-1891
- ISSN
- 0017-5749 (ISSN-L)
- 1468-3288
- OpenAlex
- W2605955022
- Cited by
- 737
- References
- 50
- Citations by year
- 2026: 81 · 2025: 112 · 2024: 128 · 2023: 105 · 2022: 93 · 2021: 83 · 2020: 68 · 2019: 44 · 2018: 17 · 2017: 4
- FWCI
- 15.93
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Gut (publishedVersion)
- PubMed (publishedVersion)
- HighWire Press Open Archive (submittedVersion)
- Funders
- GEM Community of Excellence, the University at Buffalo
- the University at Buffalo Departmental Start-Up Fund
- Natural Science Foundation of Shanghai
- National Natural Science Foundation of China
- the Peter and Tommy Fund, Inc., Buffalo, NY
- Topics
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Health Sciences › Medicine › Hepatology › Liver Disease Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Keywords
- non-alcoholic fatty liver disease, bile acids, bile acid signaling, farnesoid X receptor, FGFR4, FGF19, gut microbiota, secondary bile acids, deoxycholic acid, lithocholic acid, taurine metabolism, hepatic gene expression, high-fat diet
- MeSH terms
- Gastrointestinal Microbiome, Receptor, Farnesoid X-Activated, Animals, Bile Acids and Salts, Cholesterol 7-alpha-Hydroxylase, Female, Fibroblast Growth Factors, Humans, Male, Middle Aged, Signal Transduction, Receptors, Cytoplasmic and Nuclear, Gene Expression Profiling, Rats, Diet, High-Fat, Non-alcoholic Fatty Liver Disease
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