bims-liverm 2023-01-29 papers

Issue of 2023‒01‒29
four papers selected by
Marti Cadena Sandoval
Columbia University

World J Gastroenterol. 2023 Jan 14. 29(2): 357-366

Secondary bile acids and the biliary epithelia: The good and the bad.

Ilaria Lenci, Martina Milana, Alessandro Signorello, Giuseppe Grassi, Leonardo Baiocchi.

The biliary tract has been considered for several decades a passive system just leading the hepatic bile to the intestine. Nowadays several researches demonstrated an important role of biliary epithelia (i.e. cholangiocytes) in bile formation. The study of biliary processes therefore maintains a continuous interest since the possible important implications regarding chronic cholestatic human diseases, such as primary biliary cholangitis or primary sclerosing cholangitis. Bile acids (BAs), produced by the liver, are the most represented organic molecules in bile. The physiologic importance of BAs was initially attributed to their behavior as natural detergents but several studies now demonstrate they are also important signaling molecules. In this minireview the effect of BAs on the biliary epithelia are reported focusing in particular on secondary (deriving by bacterial manipulation of primary molecules) ones. This class of BAs is demonstrated to have relevant biological effects, ranging from toxic to therapeutic ones. In this family ursodeoxycholic and lithocholic acid present the most interesting features. The molecular mechanisms linking ursodeoxycholic acid to its beneficial effects on the biliary tract are discussed in details as well as data on the processes leading to lithocholic damage. These findings suggest that expansion of research in the field of BAs/cholangiocytes interaction may increase our understanding of cholestatic diseases and should be helpful in designing more effective therapies for biliary disorders.

Keywords: Bile acids; Biliary secretion; Cholangiocytes; Cholestasis; Lithocholic acid; Secondary bile acids; Ursodeoxycholic acid

DOI: https://doi.org/10.3748/wjg.v29.i2.357

Pediatr Int. 2023 Jan 26. e15490

Inborn Errors of Bile Acid Metabolism in Japan.

Tatsuki Mizuochi, Hajime Takei, Hiroshi Nittono, Akihiko Kimura.

Bile acids are a category of steroids biosynthesized from cholesterol in the liver. Inborn errors of their metabolism are inherited in an autosomal recessive manner, resulting in enzyme deficiencies affecting the bile acid biosynthetic pathway. These defects in the pathway cause accumulation of unusual bile acids or bile alcohols. Unusual bile acids are highly cytotoxic, causing injury to the liver. These unusual bile acids damage hepatocytes, resulting in cholestatic liver injury beginning in infancy. Except for cerebrotendinous xanthomatosis and some secondary defects, various inborn errors of bile acid metabolism (IEBAM) have been reported from Japan, affecting 8 patients including 3 with 3β-hydroxy-Δ5 -C27 -steroid dehydrogenase/isomerase deficiency, 3 with Δ4 -3-oxosteroid 5β-reductase deficiency, 1 with oxysterol 7α-hydroxylase deficiency, and 1 with bile acid-CoA: amino acid N-acyltransferase deficiency. Distinctive laboratory findings in patients with 3β-hydroxy-Δ5 -C27 -steroid dehydrogenase/isomerase deficiency, Δ4 -3-oxosteroid 5β-reductase deficiency, and oxysterol 7α-hydroxylase deficiency include normal serum γ-glutamyltransferase and total bile acids concentrations despite presence of cholestasis (elevated serum direct bilirubin) from infancy. Pediatricians and pediatric surgeons who suspect a case of IEBAM should obtain urinary and serum bile acid analyses using gas or liquid chromatography-mass spectrometry as well as genetic analyses. Available treatments include oral cholic acid, chenodeoxycholic acid, glycocholic acid, and ursodeoxycholic acid; fat-soluble vitamin supplementation; and liver transplantation. Early diagnosis and treatment can offer a good outcome.

Keywords: chenodeoxycholic acid; cholic acid; genetic analysis; neonatal cholestasis; urinary bile acid analysis

DOI: https://doi.org/10.1111/ped.15490

Biomed Pharmacother. 2023 Jan 19. pii: S0753-3322(23)00058-6. [Epub ahead of print]159 114270

Pharmacological inhibition of MEK1/2 signaling disrupts bile acid metabolism through loss of Shp and enhanced Cyp7a1 expression.

Cristy R C Verzijl, Ivo P van de Peppel, Roos E Eilers, Vincent W Bloks, Justina C Wolters, Martijn Koehorst, Niels J Kloosterhuis, Rick Havinga, Mathilde Jalving, Dicky Struik, Johan W Jonker.

The RAS-MAPK signaling pathway is one of the most frequently dysregulated pathways in human cancer. Small molecule inhibitors directed against this pathway have clinical activity in patients with various cancer types and can improve patient outcomes. However, the use of these drugs is associated with adverse effects, which can result in dose reduction or treatment interruption. A better molecular understanding of on-target, off-tumor effects may improve toxicity management. In the present study, we aimed to identify early initiating biological changes in the liver upon pharmacological inhibition of the RAS-MAPK signaling pathway. To this end, we tested the effect of MEK inhibitor PD0325901 using mice and human hepatocyte cell lines. Male C57BL/6 mice were treated with either vehicle or PD0325901 for six days, followed by transcriptome analysis of the liver and phenotypic characterization. Pharmacological MEK inhibition altered the expression of 423 genes, of which 78 were upregulated and 345 were downregulated. We identified Shp, a transcriptional repressor, and Cyp7a1, the rate-limiting enzyme in converting cholesterol to bile acids, as the top differentially expressed genes. PD0325901 treatment also affected other genes involved in bile acid regulation, which was associated with changes in the composition of plasma bile acids and composition and total levels of fecal bile acids and elevated predictive biomarkers of early liver toxicity. In conclusion, short-term pharmacological MEK inhibition results in profound changes in bile acid metabolism, which may explain some of the clinical adverse effects of pharmacological inhibition of the RAS-MAPK pathway, including gastrointestinal complications and hepatotoxicity.

Keywords: Bile acid metabolism; Cancer treatment; Liver toxicity; MEK inhibition; RAS-MAPK signaling

DOI: https://doi.org/10.1016/j.biopha.2023.114270

Ecotoxicol Environ Saf. 2023 Jan 24. pii: S0147-6513(23)00077-5. [Epub ahead of print]252 114573

The impact of subchronic ozone exposure on serum metabolome and the mechanisms of abnormal bile acid and arachidonic acid metabolisms in the liver.

Jiao Zhao, Qingcheng Yang, Zhiyuan Liu, Pengfei Xu, Lei Tian, Jun Yan, Kang Li, Bencheng Lin, Liping Bian, Zhuge Xi, Xiaohua Liu.

Ambient ozone (O3) pollution can induce respiratory and cardiovascular toxicity. However, its impact on the metabolome and the underlying mechanisms remain unclear. This study first investigated the serum metabolite changes in rats exposed to 0.5 ppm O3 for 3 months using untargeted metabolomic approach. Results showed chronic ozone exposure significantly altered the serum levels of 34 metabolites with potential increased risk of digestive, respiratory and cardiovascular disease. Moreover, bile acid synthesis and secretion, and arachidonic acid (AA) metabolism became the most prominent affected metabolic pathways after O3 exposure. Further studies on the mechanisms found that the elevated serum toxic bile acid was not due to the increased biosynthesis in the liver, but the reduced reuptake from the portal vein to hepatocytes owing to repressed Ntcp and Oatp1a1, and the decreased bile acid efflux in hepatocytes as a results of inhibited Bsep, Ostalpha and Ostbeta. Meanwhile, decreased expressions of detoxification enzyme of SULT2A1 and the important regulators of FXR, PXR and HNF4α also contributed to the abnormal bile acids. In addition, O3 promoted the conversion of AA into thromboxane A2 (TXA2) and 20-hydroxyarachidonic acid (20-HETE) in the liver by up-regulation of Fads2, Cyp4a and Tbxas1 which resulting in decreased AA and linoleic acid (LA), and increased thromboxane B2 (TXB2) and 20-HETE in the serum. Furthermore, apparent hepatic chronic inflammation, fibrosis and abnormal function were found in ozone-exposed rats. These results indicated chronic ozone exposure could alter serum metabolites by interfering their metabolism in the liver, and inducing liver injury to aggravate metabolic disorders.

Keywords: Liver injury; Metabolic pathway; Metabolomics; Ozone; Serum

DOI: https://doi.org/10.1016/j.ecoenv.2023.114573