bims-liverm 2023-05-07 papers

Issue of 2023–05–07
five papers selected by

Cell Biosci. 2023 Apr 29. 13(1): 77

Bile acid-mediated signaling in cholestatic liver diseases.

Chronic cholestatic liver diseases, such as primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), are associated with bile stasis and gradually progress to fibrosis, cirrhosis, and liver failure, which requires liver transplantation. Although ursodeoxycholic acid is effective in slowing the disease progression of PBC, it has limited efficacy in PSC patients. It is challenging to develop effective therapeutic agents due to the limited understanding of disease pathogenesis. During the last decade, numerous studies have demonstrated that disruption of bile acid (BA) metabolism and intrahepatic circulation promotes the progression of cholestatic liver diseases. BAs not only play an essential role in nutrition absorption as detergents but also play an important role in regulating hepatic metabolism and modulating immune responses as key signaling molecules. Several excellent papers have recently reviewed the role of BAs in metabolic liver diseases. This review focuses on BA-mediated signaling in cholestatic liver disease.

Keywords: Bile acid receptors; Bile acids; Cholestasis; FXR; S1PR2; TGR5

DOI: https://doi.org/10.1186/s13578-023-01035-1

JHEP Rep. 2023 May;5(5): 100714

Pathological bile acid concentrations in chronic cholestasis cause adipose mitochondrial defects.

Weinan Zhou, Philip VanDuyne, Chi Zhang, Yushan Liu, Ryan Riessen, Maribel Barragan, Blair M Rowitz, Margarita Teran-Garcia, Stephen A Boppart, Sayeepriyadarshini Anakk.

Background & Aims: Although fat loss is observed in patients with cholestasis, how chronically elevated bile acids (BAs) impact white and brown fat depots remains obscure.
Methods: To determine the direct effect of pathological levels of BAs on lipid accumulation and mitochondrial function, primary white and brown adipocyte cultures along with fat depots from two separate mouse models of cholestatic liver diseases, namely (i) genetic deletion of farnesoid X receptor (Fxr); small heterodimer (Shp) double knockout (DKO) and (ii) injury by 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC), were used.
Results: As expected, cholestatic mice accumulate high systemic BA levels and exhibit fat loss. Here, we demonstrate that chronic exposure to pathological BA levels results in mitochondrial dysfunction and defective thermogenesis. Consistently, both DKO and DDC-fed mice exhibit lower body temperature. Importantly, thermoneutral (30 °C) housing of the cholestatic DKO mice rescues the decrease in brown fat mass, and the expression of genes responsible for lipogenesis and regulation of mitochondrial function. To overcome systemic effects, primary adipocyte cultures were treated with pathological BA concentrations. Mitochondrial permeability and respiration analysis revealed that BA overload is sufficient to reduce mitochondrial function in primary adipocytes, which is not as a result of cytotoxicity. Instead, we found robust reductions in uncoupling protein 1 (Ucp1), PR domain containing 16 (Prdm16), and deiodinase, iodothyronine, type II (Dio2) transcripts in brown adipocytes upon treatment with chenodeoxycholic acid, whereas taurocholic acid led to the suppression of Dio2 transcript. This BA-mediated decrease in transcripts was alleviated by pharmacological activation of UCP1.
Conclusions: High concentrations of BAs cause defective thermogenesis by reducing the expression of crucial regulators of mitochondrial function, including UCP1, which may explain the clinical features of hypothermia and fat loss observed in patients with cholestatic liver diseases.
Impact and Implications: We uncover a detrimental effect of chronic bile acid overload on adipose mitochondrial function. Pathological concentration of different BAs reduces the expression of distinct genes involved in energy expenditure, which can be mitigated with pharmacological UCP1 activation.

Keywords: Adipose tissue; Bile acid; Cholestasis; Mitochondrial function

DOI: https://doi.org/10.1016/j.jhepr.2023.100714

Cell Mol Gastroenterol Hepatol. 2023 May 03. pii: S2352-345X(23)00061-9. [Epub ahead of print]

Organic anion transporting polypeptide (OATP) 1B3 is a significant transporter for hepatic uptake of conjugated bile acids in humans.

Qiong Pan, Guanyu Zhu, Ziqian Xu, Jinfei Zhu, Jiafeng Ouyang, Yao Tong, Nan Zhao, Xiaoxun Zhang, Ying Cheng, Liangjun Zhang, Ya Tan, Jianwei Li, Chengcheng Zhang, Wensheng Chen, Shi-Ying Cai, James L Boyer, Jin Chai.

BACKGROUND & AIMS: OATP1B3/SLCO1B3 is a human liver-specific transporter for the clearance of endogenous compounds (e.g. bile acid/BA) and xenobiotics. The functional role of OATP1B3 in humans has not been characterized as SLCO1B3 is poorly conserved among species without mouse orthologs.
METHODS: Slc10a1-knockout (Slc10a1-/-), Slc10a1hSLCO1B3 (endogenous mouse Slc10a1 promoter-driven human-SLCO1B3 expression in Slc10a1-/- mice), and human SLCO1B3 liver-specific transgenic (hSLCO1B3-LTG) mice were generated and challenged with 0.1% ursodeoxycholic-acid (UDCA), 1% cholic-acid (CA) diet or bile-duct ligation (BDL) for functional studies. Primary hepatocytes and hepatoma-PLC/RPF/5 cells were used for mechanistic studies.
RESULTS: Serum BA levels in Slc10a1-/- mice were substantially increased with or without 0.1% UDCA-feeding compared to WT-mice. This increase was attenuated in Slc10a1hSLCO1B3-mice, indicating that OATP1B3 functions as a significant hepatic BA-uptake transporter. In vitro assay using primary hepatocytes from WT, Slc10a1-/-, and Slc10a1hSLCO1B3-mice indicated that OATP1B3 has a similar capacity in taking up taurocholate/TCA as Ntcp. Furthermore, TCA-induced bile flow was significantly impaired in Slc10a1-/- mice but partially recovered in Slc10a1hSLC01B3-mice, indicating that OATP1B3 can partially compensate the NTCP function in vivo. Liver-specific overexpression of OATP1B3 markedly increased the level of hepatic conjugated BA and cholestatic liver injury in 1% CA-fed and BDL mice. Mechanistic studies revealed that conjugated BAs stimulated Ccl2 and Cxcl2 in hepatocytes to increase hepatic neutrophil infiltration and proinflammatory cytokine production (e.g. IL-6), which activated STAT3 to repress OATP1B3 expression by binding to its promoter.
CONCLUSIONS: Human OATP1B3 is a significant BA uptake transporter, and can partially compensate Ntcp for conjugated BA uptake in mice. Its downregulation in cholestasis is an adaptive protective response.

Keywords: Bile acid transporter; Cholestasis; OATP1B3; Proinflammatory cytokine

DOI: https://doi.org/10.1016/j.jcmgh.2023.04.007

Genome Biol. 2023 04 30. 24(1): 98

Caloric restriction remodels the hepatic chromatin landscape and bile acid metabolism by modulating the gut microbiota.

Yun Fan, Hong Qian, Meijia Zhang, Chengzhe Tao, Zhi Li, Wenkai Yan, Yuna Huang, Yan Zhang, Qiaoqiao Xu, Xinru Wang, Paul A Wade, Yankai Xia, Yufeng Qin, Chuncheng Lu.

BACKGROUND: Caloric restriction (CR) has been known to promote health by reprogramming metabolism, yet little is known about how the epigenome and microbiome respond during metabolic adaptation to CR.
RESULTS: We investigate chromatin modifications, gene expression, as well as alterations in microbiota in a CR mouse model. Collectively, short-term CR leads to altered gut microbial diversity and bile acid metabolism, improving energy expenditure. CR remodels the hepatic enhancer landscape at genomic loci that are enriched for binding sites for signal-responsive transcription factors, including HNF4α. These alterations reflect a dramatic reprogramming of the liver transcriptional network, including genes involved in bile acid metabolism. Transferring CR gut microbiota into mice fed with an obesogenic diet recapitulates the features of CR-related bile acid metabolism along with attenuated fatty liver.
CONCLUSIONS: These findings suggest that CR-induced microbiota shapes the hepatic epigenome followed by altered expression of genes responsible for bile acid metabolism.

Keywords: Bile acid metabolism; Caloric restriction; Gut microbiota; Hepatic epigenome; Metabolic adaptation

DOI: https://doi.org/10.1186/s13059-023-02938-5

Mol Pharm. 2023 May 03.

Characterization of Bile Acid Sulfate Conjugates as Substrates of Human Organic Anion Transporting Polypeptides.

Christine C Orozco, Mikko Neuvonen, Yi-An Bi, Matthew A Cerny, Sumathy Mathialagan, Laurie Tylaska, Brian Rago, Chester Costales, Amanda King-Ahmad, Mikko Niemi, A David Rodrigues.

Drug interactions involving the inhibition of hepatic organic anion transporting polypeptides (OATPs) 1B1 and OATP1B3 are considered important. Therefore, we sought to study various sulfated bile acids (BA-S) as potential clinical OATP1B1/3 biomarkers. It was determined that BA-S [e.g., glycochenodeoxycholic acid 3-O-sulfate (GCDCA-S) and glycodeoxycholic acid 3-O-sulfate (GDCA-S)] are substrates of OATP1B1, OATP1B3, and sodium-dependent taurocholic acid cotransporting polypeptide (NTCP) transfected into human embryonic kidney 293 cells, with minimal uptake evident for other solute carriers (SLCs) like OATP2B1, organic anion transporter 2, and organic cation transporter 1. It was also shown that BA-S uptake by plated human hepatocytes (PHH) was inhibited (≥96%) by a pan-SLC inhibitor (rifamycin SV), and there was greater inhibition (≥77% versus ≤12%) with rifampicin (OATP1B1/3-selective inhibitor) than a hepatitis B virus myristoylated-preS1 peptide (NTCP-selective inhibitor). Estrone 3-sulfate was also used as an OATP1B1-selective inhibitor. In this instance, greater inhibition was observed with GDCA-S (76%) than GCDCA-S (52%). The study was expanded to encompass the measurement of GCDCA-S and GDCA-S in plasma of SLCO1B1 genotyped subjects. The geometric mean GDCA-S concentration was 2.6-fold (90% confidence interval 1.6, 4.3; P = 2.1 × 10-4) and 1.3-fold (1.1, 1.7; P = 0.001) higher in individuals homozygous and heterozygous for the SLCO1B1 c.521T > C loss-of-function allele, respectively. For GCDCA-S, no significant difference was noted [1.2-fold (0.8, 1.7; P = 0.384) and 0.9-fold (0.8, 1.1; P = 0.190), respectively]. This supported the in vitro data indicating that GDCA-S is a more OATP1B1-selective substrate (versus GCDCA-S). It is concluded that GCDCA-S and GDCA-S are viable plasma-based OATP1B1/3 biomarkers, but they are both less OATP1B1-selective when compared to their corresponding 3-O-glucuronides (GCDCA-3G and GDCA-3G). Additional studies are needed to determine their utility versus more established biomarkers, such as coproporphyrin I, for assessing inhibitors with different OATP1B1 (versus OATP1B3) inhibition signatures.

Keywords: biomarker; drug interaction; organic anion transporting polypeptide; sulfated bile acids

DOI: https://doi.org/10.1021/acs.molpharmaceut.3c00040