bims-liverm 2023-02-26 papers

Issue of 2023–02–26
five papers selected by

Liver Res. 2022 Dec;6(4): 276-283

Effects of apical sodium-bile acid transporter inhibitor and obeticholic acid co-treatment in experimental non-alcoholic steatohepatitis.

David J Matye, Xuan Qin, Mohammad Nazmul Hasan, Lijie Gu, Yung-Dai Clayton, Feng Li, Tiangang Li.

Background and aims: Several bile acids-based monotherapies have been developed for non-alcoholic steatohepatitis (NASH) treatment but clinical trial findings suggest that they do not satisfactorily improve NASH and liver fibrosis in many patients. Recently, we have shown that combining a gut-restricted apical sodium-bile acid transporter (ASBT) inhibitor GSK2330672 (GSK) with adeno-associated virus (AAV)-mediated liver fibroblast growth factor 15 (FGF15) overexpression provides significantly improved efficacy than either single treatment against NASH and liver fibrosis in a high fat, cholesterol, and fructose (HFCFr) diet-induced NASH mouse model. The beneficial effects of the combined treatment can be attributed to the markedly reduced bile acid pool that reduces liver bile acid burden and intestinal lipid absorption. The aim of this study is to further investigate if combining GSK treatment with the orally bioavailable obeticholic acid (OCA), which induces endogenous FGF15 and inhibits hepatic bile acid synthesis, can achieve similar anti-NASH effect as the GSK+AAV-FGF15 co-treatment in HFCFr-diet-fed mice.
Materials and methods: Male C57BL/6J mice were fed HFCFr diet to induce NASH and liver fibrosis. The effect of GSK, OCA, and GSK+OCA treatments on NASH development was compared and contrasted among all groups.
Results: Findings from this study showed that the GSK+OCA co-treatment did not cause persistent reduction of obesity over a 12-week treatment period. Neither single treatment nor the GSK+OCA co-treatment reduce hepatic steatosis, but all three treatments reduced hepatic inflammatory cytokines and fibrosis by a similar magnitude. The GSK+OCA co-treatment caused a higher degree of total bile acid pool reduction (~55%) than either GSK or OCA treatment alone. However, such bile acid pool reduction was insufficient to cause increased fecal lipid loss. The GSK+OCA co-treatment prevented GSK-mediated induction of hepatic cholesterol 7alpha-hydroxylase but failed to induce ileal FGF15 expression. GSK did not reduce gallbladder OCA amount in the GSK+OCA group compared to the OCA group, suggesting that ASBT inhibition does not reduce hepatic OCA distribution.
Conclusions: Unlike the GSK+AAV-FGF15 co-treatment, the GSK+OCA co-treatment does not provide improved efficacy against NASH and liver fibrosis than either single treatment in mice. The lack of synergistic effect may be partly attributed to the moderate reduction of total bile acid pool and the lack of high level of FGF15 exposure as seen in the GSK+AAV-FGF15 co-treatment.

Keywords: Apical sodium-bile acid transporter (ASBT); Bile acids; Farnesoid X receptor (FXR); Fibroblast growth factor 15 (FGF15); Liver fibrosis; Non-alcoholic steatohepatitis (NASH)

DOI: https://doi.org/10.1016/j.livres.2022.11.002

Front Neurosci. 2023 ;17 1123967

Liver's influence on the brain through the action of bile acids.

Xin Yi Yeo, Li Yang Tan, Woo Ri Chae, Dong-Yup Lee, Yong-An Lee, Torsten Wuestefeld, Sangyong Jung.

The liver partakes as a sensor and effector of peripheral metabolic changes and a regulator of systemic blood and nutrient circulation. As such, abnormalities arising from liver dysfunction can influence the brain in multiple ways, owing to direct and indirect bilateral communication between the liver and the brain. Interestingly, altered bile acid composition resulting from perturbed liver cholesterol metabolism influences systemic inflammatory responses, blood-brain barrier permeability, and neuron synaptic functions. Furthermore, bile acids produced by specific bacterial species may provide a causal link between dysregulated gut flora and neurodegenerative disease pathology through the gut-brain axis. This review will cover the role of bile acids-an often-overlooked category of active metabolites-in the development of neurological disorders associated with neurodegeneration. Further studies into bile acid signaling in the brain may provide insights into novel treatments against neurological disorders.

Keywords: bile acid; brain; gut microbiome; liver; neurodegeneration

DOI: https://doi.org/10.3389/fnins.2023.1123967

Cells. 2023 Feb 06. pii: 526. [Epub ahead of print]12(4):

Conjugated Bile Acids Promote Lymphangiogenesis by Modulation of the Reactive Oxygen Species-p90RSK-Vascular Endothelial Growth Factor Receptor 3 Pathway.

Priyanka Banerjee, Subhashree Kumaravel, Sukanya Roy, Niyanshi Gaddam, Johnny Odeh, Kayla J Bayless, Shannon Glaser, Sanjukta Chakraborty.

Conjugated bile acids (BA) are significantly elevated in several liver pathologies and in the metastatic lymph node (LN). However, the effects of BAs on pathological lymphangiogenesis remains unknown. The current study explores the effects of BAs on lymphangiogenesis. BA levels were elevated in the LN and serum of Mdr2-/- mice (model of sclerosing cholangitis) compared to control mice. Liver and LN tissue sections showed a clear expansion of the lymphatic network in Mdr2-/- mice, indicating activated lymphangiogenic pathways. Human lymphatic endothelial cells (LECs) expressed BA receptors and a direct treatment with conjugated BAs enhanced invasion, migration, and tube formation. BAs also altered the LEC metabolism and upregulated key metabolic genes. Further, BAs induced the production of reactive oxygen species (ROS), that in turn phosphorylated the redox-sensitive kinase p90RSK, an essential regulator of endothelial cell dysfunction and oxidative stress. Activated p90RSK increased the SUMOylation of the Prox1 transcription factor and enhanced VEGFR3 expression and 3-D LEC invasion. BA-induced ROS in the LECs, which led to increased levels of Yes-associated protein (YAP), a lymphangiogenesis regulator. The suppression of cellular YAP inhibited BA-induced VEGFR3 upregulation and lymphangiogenic mechanism. Overall, our data shows the expansion of the lymphatic network in presclerotic liver disease and establishes a novel mechanism whereby BAs promote lymphangiogenesis.

Keywords: bile acids; growth factor signaling; lymphangiogenesis; lymphatic endothelial cells; oxidative stress

DOI: https://doi.org/10.3390/cells12040526

Biomark Res. 2023 Feb 18. 11(1): 20

The essential roles of FXR in diet and age influenced metabolic changes and liver disease development: a multi-omics study.

Guiyan Yang, Prasant K Jena, Ying Hu, Lili Sheng, Shin-Yu Chen, Carolyn M Slupsky, Ryan Davis, Clifford G Tepper, Yu-Jui Yvonne Wan.

BACKGROUND: Aging and diet are risks for metabolic diseases. Bile acid receptor farnesoid X receptor (FXR) knockout (KO) mice develop metabolic liver diseases that progress into cancer as they age, which is accelerated by Western diet (WD) intake. The current study uncovers the molecular signatures for diet and age-linked metabolic liver disease development in an FXR-dependent manner.
METHODS: Wild-type (WT) and FXR KO male mice, either on a healthy control diet (CD) or a WD, were euthanized at the ages of 5, 10, or 15 months. Hepatic transcriptomics, liver, serum, and urine metabolomics as well as microbiota were profiled.
RESULTS: WD intake facilitated hepatic aging in WT mice. In an FXR-dependent manner, increased inflammation and reduced oxidative phosphorylation were the primary pathways affected by WD and aging. FXR has a role in modulating inflammation and B cell-mediated humoral immunity which was enhanced by aging. Moreover, FXR dictated neuron differentiation, muscle contraction, and cytoskeleton organization in addition to metabolism. There were 654 transcripts commonly altered by diets, ages, and FXR KO, and 76 of them were differentially expressed in human hepatocellular carcinoma (HCC) and healthy livers. Urine metabolites differentiated dietary effects in both genotypes, and serum metabolites clearly separated ages irrespective of diets. Aging and FXR KO commonly affected amino acid metabolism and TCA cycle. Moreover, FXR is essential for colonization of age-related gut microbes. Integrated analyses uncovered metabolites and bacteria linked with hepatic transcripts affected by WD intake, aging, and FXR KO as well as related to HCC patient survival.
CONCLUSION: FXR is a target to prevent diet or age-associated metabolic disease. The uncovered metabolites and microbes can be diagnostic markers for metabolic disease.

Keywords: Bile acid; Bile acid receptor; Gut microbiota; Hepatocellular carcinoma; Liver; Metabolic disease; Nonalcoholic fatty liver disease; Nonalcoholic steatohepatitis

DOI: https://doi.org/10.1186/s40364-023-00458-9

Clin Mol Hepatol. 2023 Feb 20.

Taurocholic Acid Promotes Hepatic Stellate Cell Activation via S1PR2/p38 MAPK/YAP Signaling under Cholestatic Conditions.

Jing Yang, Xujiao Tang, Zhu Liang, Mingzhu Chen, Lixin Sun.

Background and Aims: Disrupted bile acid regulation and accumulation in the liver can contribute to progressive liver damage and fibrosis. However, the effect of bile acids on the activation of hepatic stellate cells (HSC) is unknown. This study investigated the effect of bile acids on HSC activation during liver fibrosis, and examined the underlying mechanisms.
Methods: The immortalized HSCs, LX-2 and JS-1cells, were used for the in vitro study. In vivo, the adeno-associated virus AAV-sh-S1PR2, and JTE-013 were used to pharmacologically inhibit the activity of S1PR2 in a murine model of fibrosis induced by a 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet. Histological and biochemical analyses were performed to study the involvement of S1PR2 in the regulation of fibrogenic factors as well as the activation properties of HSC.
Results: S1PR2 was the predominant S1PR expressed in HSCs and was upregulated during TCA stimulation and in cholestatic liver fibrosis mice. TCA-induced HSC proliferation, migration and contraction and extracellular matrix protein secretion were inhibited by JTE-013, and a specific shRNA targeting S1PR2 in LX-2 and JS-1 cells. Meanwhile, treatment with JTE-013 or S1PR2 deficiency significantly attenuated liver histopathological injury, collagen accumulation, and the expression of fibrogenesis-associated genes in mice fed a DDC diet. Furthermore, TCA-mediated activation of HSCs through S1PR2 was closely related to the yes-associated protein (YAP) signaling pathway via p38 mitogen-activated protein kinase (p38 MAPK).
Conclusions: TCA-induced activation of the S1PR2/p38 MAPK/YAP signaling pathways plays a vital role in regulating HSC activation which might be therapeutically relevant for targeting cholestatic liver fibrosis.

Keywords: S1PR2; YAP; cholestatic liver fibrosis; hepatic stellate cells; Taurocholic acid

DOI: https://doi.org/10.3350/cmh.2022.0327