bims-liverm 2023-03-05 papers

Issue of 2023–03–05
six papers selected by

Eur J Med Chem. 2023 Jan 25. pii: S0223-5234(23)00058-2. [Epub ahead of print]250 115143

The discovery of 12β-methyl-17-epi-18-nor-bile acids as potent and selective TGR5 agonists.

Andreas Luxenburger, Lawrence D Harris, Elizabeth M Ure, Wanting Jiao, Anthony D Woolhouse, Scott A Cameron, Alex Weymouth-Wilson, Richard H Furneaux, Janet L Pitman, Simon F R Hinkley.

Recent discoveries have demonstrated that the physiological function of bile acids extends to the regulation of diverse signaling processes through interactions with nuclear and G protein-coupled receptors, most notably the Farnesoid-X nuclear receptor (FXR) and the G protein-coupled bile acid receptor 1 (GPBAR1, also known as TGR5). Targeting such signaling pathways pharmacologically, i.e. with bile acid-derived therapeutics, presents great potential for the treatment of various metabolic, inflammatory immune, liver, and neurodegenerative diseases. Here we report the discovery of two potent and selective TGR5 agonists (NZP196 and 917). These compounds are the taurine conjugates of 6α-ethyl-substituted 12β-methyl-18-nor-bile acids with the side chain being located on the α-face of the steroid scaffold. The compounds emerged from a screening effort of a diverse library of 12β-methyl-18-nor-bile acids that were synthesized from 12β-methyl-18-nor-chenodeoxycholic acid and its C17-epimer. Upon testing for FXR activity, both compounds were found to be inactive, thus revealing selectivity for TGR5.

Keywords: 12β-Methyl-18-nor-bile acids; Bile acid; FXR; Farnesoid X receptor; G protein-coupled bile acid receptor 1; GPBAR1; In vitro efficacy; Molecular docking; SEAP reporter assay; Structure−activity relationship; TGR5 agonists

DOI: https://doi.org/10.1016/j.ejmech.2023.115143

Gut Microbes. 2023 Jan-Dec;15(1):15(1): 2183690

Cholestasis impairs gut microbiota development and bile salt hydrolase activity in preterm neonates.

Lauren E Lynch, Amy B Hair, Krishnakant G Soni, Heeju Yang, Laura A Gollins, Monica Narvaez-Rivas, Kenneth D R Setchell, Geoffrey A Preidis.

Cholestasis refers to impaired bile flow from the liver to the intestine. In neonates, cholestasis causes poor growth and may progress to liver failure and death. Normal bile flow requires an intact liver-gut-microbiome axis, whereby liver-derived primary bile acids are transformed into secondary bile acids. Microbial bile salt hydrolase (BSH) enzymes are responsible for the first step, deconjugating glycine- and taurine-conjugated primary bile acids. Cholestatic neonates often are treated with the potent choleretic bile acid ursodeoxycholic acid (UDCA), although interactions between UDCA, gut microbes, and other bile acids are poorly understood. To gain insight into how the liver-gut-microbiome axis develops in extreme prematurity and how cholestasis alters this maturation, we conducted a nested case-control study collecting 124 stool samples longitudinally from 24 preterm infants born at mean 27.2 ± 1.8 weeks gestation and 946 ± 249.6 g, half of whom developed physiologic cholestasis. Samples were analyzed by whole metagenomic sequencing, in vitro BSH enzyme activity assays optimized for low biomass fecal samples, and quantitative mass spectrometry to measure the bile acid metabolome. In extremely preterm neonates, acquisition of the secondary bile acid biosynthesis pathway and BSH genes carried by Clostridium perfringens are the most prominent features of early microbiome development. Cholestasis interrupts this developmental pattern. BSH gene abundance and enzyme activity are profoundly reduced in cholestatic neonates, resulting in decreased quantities of unconjugated bile acids. UDCA restores total fecal bile acid levels in cholestatic neonates, but this is due to a 522-fold increase in fecal UDCA. A majority of bile acids in early development are atypical positional and stereo-isomers of bile acids. We report novel associations linking isomeric bile acids and BSH activity to neonatal growth trajectories. These data highlight deconjugation of bile acids as a key microbial function that is acquired in early neonatal development and impaired by cholestasis.

Keywords: Microbiome; bile acids; bile salt hydrolase; cholestasis; growth; neonate; premature infant; ursodeoxycholic acid

DOI: https://doi.org/10.1080/19490976.2023.2183690

Acta Med Okayama. 2023 Feb;77(1): 29-36

Increased Glycine-conjugated and Unconjugated Bile Acid Levels Associated with Aggravation of Nonalcoholic Steatohepatitis and Cardiovascular Disease in SHRSP5/Dmcr Rat.

Shusei Yamamoto, Ikumi Sato, Moe Fujii, Mai Kakimoto, Koki Honma, Natsumi Akiyama, Miku Sakai, Natsuki Fukuhama, Shota Kumazaki, Satoshi Hirohata, Kazuya Kitamori, Yukio Yamori, Shogo Watanabe.

The SHRSP5/Dmcr is a useful animal model for the development of nonalcoholic steatohepatitis (NASH) pathology when fed a high-fat, high-cholesterol diet, and further drug interventions can lead to concomitant cardiovascular disease. While SHRSP5/Dmcr rats have been used for basic research related to NASH, details of their bile acid metabolism in this condition are unknown. In this study, we aimed to clarify the changes in the serum bile acid (BA) fractions associated with NASH and found that glycine-conjugated and unconjugated bile acid increased with worsening NASH and cardiovascular disease while taurine-conjugated BA relatively decreased.

Keywords: SHRSP5/Dmc; cardiovascular disease; glycine-conjugated bile acids; nonalcoholic steatohepatitis; unconjugated bile acids

DOI: https://doi.org/10.18926/AMO/64358

J Phys Chem B. 2023 Mar 02.

Mechanistic Insight into the Amyloid Fibrillation Inhibition of Hen Egg White Lysozyme by Three Different Bile Acids.

Nidhi Anilkumar Jamuna, Adithya Kamalakshan, Bhupendra Ramesh Dandekar, Anu Maria Chittilappilly Devassy, Jagannath Mondal, Sarthak Mandal.

Amyloid aggregation of protein is linked to many neurodegenerative diseases. Identification of small molecules capable of targeting amyloidogenic proteins has gained significant importance. Introduction of hydrophobic and hydrogen bonding interactions through site-specific binding of small molecular ligand to protein can effectively modulate the protein aggregation pathway. Here, we investigate the possible roles of three different bile acids, cholic acid (CA), taurocholic acid (TCA), and lithocholic acid (LCA) with varying hydrophobic and hydrogen bonding properties in inhibiting protein fibrillation. Bile acids are an important class of steroid compounds that are synthesized in the liver from cholesterol. Increasing evidence suggests that altered taurine transport, cholesterol metabolism, and bile acid synthesis have strong implications in Alzheimer's disease. We find that the hydrophilic bile acids, CA and TCA (taurine conjugated form of CA), are substantially more efficient inhibitors of lysozyme fibrillation than the most hydrophobic secondary bile acid LCA. Although LCA binds more strongly with the protein and masks the Trp residues more prominently through hydrophobic interactions, the lesser extent of hydrogen bonding interactions at the active site has made LCA a relatively weaker inhibitor of HEWL aggregation than CA and TCA. The introduction of a greater number of hydrogen bonding channels by CA and TCA with several key amino acid residues which are prone to form oligomers and fibrils has weakened the protein's internal hydrogen bonding capabilities for undergoing amyloid aggregation.

DOI: https://doi.org/10.1021/acs.jpcb.3c00274

J Biol Chem. 2023 Feb 24. pii: S0021-9258(23)00202-8. [Epub ahead of print] 103070

My lifelong dedication to bile acid research.

JohnY L Chiang.

It is a great honor to be invited to write a reflection of my lifelong bile acid research for the Journal of Biological Chemistry, the premier biochemistry journal in which I am proud to have published 24 manuscripts. I published 21 manuscripts in the Journal of Lipid Research, also a journal of American Society of Biochemistry and Molecular Biology. I started my reflection from my early education in Taiwan, my coming to America for graduate study, my postdoctoral training in cytochrome P450 research, and my lifelong bile acid research career at the not so "visible" Northeast Ohio Medical University. I have witnesses and help to transform this sleepy rural medical school to a well-funded powerhouse in liver research. Writing this reflection of my long, exciting, and rewarding journey in bile acid research brought back many good memories. I am proud of my scientific contribution. I attribute my lifelong academic success to working hard, perseverance, good mentoring, and networking. I hope that this reflection of my academic career may provide guidance to younger investigators who are pursuing academic teaching and research and might inspire the next generation of researchers in biochemistry and metabolic diseases.

Keywords: Bile acid synthesis; CYP7A1; FXR; TGR5; cholesterol 7α-hydroxylase; metabolism and regulation

DOI: https://doi.org/10.1016/j.jbc.2023.103070

Gut Liver. 2023 Mar 02.

GATA4 Forms a Positive Feedback Loop with CDX2 to Transactivate MUC2 in Bile Acids-Induced Gastric Intestinal Metaplasia.

Xiaofang Yang, Ting Ye, Li Rong, Hong Peng, Jin Tong, Xiao Xiao, Xiaoqiang Wan, Jinjun Guo.

Background/Aims: Gastric intestinal metaplasia (GIM), a common precancerous lesion of gastric cancer, can be caused by bile acid reflux. GATA binding protein 4 (GATA4) is an intestinal transcription factor involved in the progression of gastric cancer. However, the expression and regulation of GATA4 in GIM has not been clarified.
Methods: The expression of GATA4 in bile acid-induced cell models and human specimens was examined. The transcriptional regulation of GATA4 was investigated by chromatin immunoprecipitation and luciferase reporter gene analysis. An animal model of duodenogastric reflux was used to confirm the regulation of GATA4 and its target genes by bile acids.
Results: GATA4 expression was elevated in bile acid-induced GIM and human specimens. GATA4 bound to the promoter of mucin 2 (MUC2) and stimulate its transcription. GATA4 and MUC2 expression was positively correlated in GIM tissues. Nuclear transcription factor-κB activation was required for the upregulation of GATA4 and MUC2 in bile acid-induced GIM cell models. GATA4 and caudal-related homeobox 2 (CDX2) reciprocally transactivated each other to drive the transcription of MUC2. In chenodeoxycholic acid-treated mice, MUC2, CDX2, GATA4, p50, and p65 expression levels were increased in the gastric mucosa.
Conclusions: GATA4 is upregulated and can form a positive feedback loop with CDX2 to transactivate MUC2 in GIM. NF-κB signaling is involved in the upregulation of GATA4 by chenodeoxycholic acid.

Keywords: GATA4 transcription factor; Intestinal metaplasia; NF-κB signaling; Transcriptional activation

DOI: https://doi.org/10.5009/gnl220394