Conjugated secondary 12α-hydroxylated bile acids promote liver fibrogenesis

Abstract

Background: Significantly elevated serum and hepatic bile acid (BA) concentrations have been known to occur in patients with liver fibrosis. However, the roles of different BA species in liver fibrogenesis are not fully understood. Methods: We quantitatively measured blood BA concentrations in nonalcoholic steatohepatitis (NASH) patients with liver fibrosis and healthy controls. We characterized BA composition in three mouse models induced by carbon tetrachloride (CCl 4 ), streptozotocin-high fat diet (STZ-HFD), and long term HFD, respectively. The molecular mechanisms underlying the fibrosis-promoting effects of BAs were investigated in cell line models, a 3D co-culture system, and a Tgr5 (HSC-specific) KO mouse model. Findings: We found that a group of conjugated 12a-hydroxylated (12a-OH) BAs, such as taurodeoxycholate (TDCA) and glycodeoxycholate (GDCA), significantly increased in NASH patients and liver fibrosis mouse models. 12a-OH BAs significantly increased HSC proliferation and protein expression of fibrosis-related markers. Administration of TDCA and GDCA directly activated HSCs and promoted liver fibrogenesis in mouse models. Blockade of BA binding to TGR5 or inhibition of ERK1/2 and p38 MAPK signaling both significantly attenuated the BA-induced fibrogenesis. Liver fibrosis was attenuated in mice with Tgr5 depletion. Interpretation: Increased hepatic concentrations of conjugated 12a-OH BAs significantly contributed to liver fibrosis via TGR5 mediated p38MAPK and ERK1/2 signaling. Strategies to antagonize TGR5 or inhibit ERK1/2 and p38 MAPK signaling may effectively prevent or reverse liver fibrosis.

Mulberrin confers protection against hepatic fibrosis by Trim31/Nrf2 signaling

“…5B ). LPS is frequently used to induce inflammatory response [ 40 ]. As expected, LPS-enhanced IL-1β, TNF-α, IL-6, IL-18, MCP-1 and CXCL-10 in L02 cells or supernatants were considerably mitigated by Mul ( Fig.…”

Flaxseed Powder Attenuates Non-Alcoholic Steatohepatitis via Modulation of Gut Microbiota and Bile Acid Metabolism through Gut–Liver Axis

“…However, we also found that two 12αOH BAs, DCA and NorCA, were significantly increased. Evidence has shown that DCA and LCA, as secondary Bas, were more effective in activating TGR5 than primary BAs (CA and CDCA) [ 11 , 55 ]. Therefore, the gut microbe-dependent production of DCA, as well as its enterohepatic circulation and conjugation in the liver, is of profound significance in liver fibrogenesis.…”

“…Concentrations of fecal Bas were measured according to previously reported methods [ 11 ]. In short, the Waters ACQUITY ultra-performance LC system and Waters XEVO TQ-S mass spectrometer with an ESI source controlled by MassLynx 4.1 software (Waters, Milford, MA) were used for analyzing fecal extracts and BA reference standards.…”

“…CYP8B1 activity determines the ratio of CA to CDCA [ 10 ]. The structural difference between CA and CDCA is that CA and its derivatives have a 12α-OH that is catalyzed by CYP8B1, while CDCA and its derivatives are non-12α-OH BAs without 12-hydroxylation [ 11 ].…”

Altered bile acid glycine : taurine ratio in the progression of chronic liver disease

“…14 A group of conjugated 12α-hydroxylated (12α-OH) BAs significantly increased in NASH patients and liver fibrosis mouse models and were potential promoters of liver fibrosis. 15 Based on these, we constructed and validated several machine learning models to classify early (stage 0-2) and advanced (stage 3-4) hepatic fibrosis using BAs and clinical parameters in patients with hepatitis B and C virus infections 16,17 and NAFLD 18 patients. Furthermore, we discussed the mechanistic links between BAs and HCC and highlighted the strategies and cutting-edge technologies to target gut microbiota-dependent alterations in BA metabolism in the context of cancer therapy.…”