bims-liverm 2022-12-18 papers

bims-liverm

Biomed News

on Liver Metabolism

Issue of 2022–12–18
seven papers selected by

Identification of the Role of TGR5 in the Regulation of Leydig Cell Homeostasis.
Recent Advances in the Digestive, Metabolic and Therapeutic Effects of Farnesoid X Receptor and Fibroblast Growth Factor 19: From Cholesterol to Bile Acid Signaling.
Elevated bile acid metabolism and microbiome are associated with suppressed cell proliferation and better survival in breast cancer.
Development of a system adapted for the diagnosis and evaluation of peroxisomal disorders by measuring bile acid intermediates.
Recombinant Humanized IgG1 Antibody Promotes Reverse Cholesterol Transport through FcRn-ERK1/2-PPARα Pathway in Hepatocytes.
A High Hepatic Uptake of Conjugated Bile Acids Promotes Colorectal Cancer-Associated Liver Metastasis.
Secondary bile acid lithocholic acid attenuates neurally evoked ion transport in the rat distal colon.

Int J Mol Sci. 2022 Dec 06. pii: 15398. [Epub ahead of print]23(23):

Identification of the Role of TGR5 in the Regulation of Leydig Cell Homeostasis.

Hélène Holota, Angélique De Haze, Emmanuelle Martinot, Melusine Monrose, Jean-Paul Saru, Françoise Caira, Claude Beaudoin, David H Volle.

  Understanding the regulation of the testicular endocrine function leading to testosterone production is a major objective as the alteration of endocrine function is associated with the development of many diseases such as infertility. In the last decades, it has been demonstrated that several endogenous molecules regulate the steroidogenic pathway. Among them, bile acids have recently emerged as local regulators of testicular physiology and particularly endocrine function. Bile acids act through the nuclear receptor FXRα (Farnesoid-X-receptor alpha; NR1H4) and the G-protein-coupled bile acid receptor (GPBAR-1; TGR5). While FXRα has been demonstrated to regulate testosterone synthesis within Leydig cells, no data are available regarding TGR5. Here, we investigated the potential role of TGR5 within Leydig cells using cell culture approaches combined with pharmacological exposure to the TGR5 agonist INT-777. The data show that activation of TGR5 results in a decrease in testosterone levels. TGR5 acts through the PKA pathway to regulate steroidogenesis. In addition, our data show that TGR5 activation leads to an increase in cholesterol ester levels. This suggests that altered lipid homeostasis may be a mechanism explaining the TGR5-induced decrease in testosterone levels. In conclusion, the present work highlights the impact of the TGR5 signaling pathway on testosterone production and reinforces the links between bile acid signaling pathways and the testicular endocrine function. The testicular bile acid pathways need to be further explored to increase our knowledge of pathologies associated with impaired testicular endocrine function, such as fertility disorders.

Keywords:  TGR5; bile acids; cholesterol esters; testosterone

DOI:  https://doi.org/10.3390/ijms232315398
Nutrients. 2022 Nov 22. pii: 4950. [Epub ahead of print]14(23):

Recent Advances in the Digestive, Metabolic and Therapeutic Effects of Farnesoid X Receptor and Fibroblast Growth Factor 19: From Cholesterol to Bile Acid Signaling.

Agostino Di Ciaula, Leonilde Bonfrate, Jacek Baj, Mohamad Khalil, Gabriella Garruti, Frans Stellaard, Helen H Wang, David Q-H Wang, Piero Portincasa.

  Bile acids (BA) are amphiphilic molecules synthesized in the liver (primary BA) starting from cholesterol. In the small intestine, BA act as strong detergents for emulsification, solubilization and absorption of dietary fat, cholesterol, and lipid-soluble vitamins. Primary BA escaping the active ileal re-absorption undergo the microbiota-dependent biotransformation to secondary BA in the colon, and passive diffusion into the portal vein towards the liver. BA also act as signaling molecules able to play a systemic role in a variety of metabolic functions, mainly through the activation of nuclear and membrane-associated receptors in the intestine, gallbladder, and liver. BA homeostasis is tightly controlled by a complex interplay with the nuclear receptor farnesoid X receptor (FXR), the enterokine hormone fibroblast growth factor 15 (FGF15) or the human ortholog FGF19 (FGF19). Circulating FGF19 to the FGFR4/β-Klotho receptor causes smooth muscle relaxation and refilling of the gallbladder. In the liver the binding activates the FXR-small heterodimer partner (SHP) pathway. This step suppresses the unnecessary BA synthesis and promotes the continuous enterohepatic circulation of BAs. Besides BA homeostasis, the BA-FXR-FGF19 axis governs several metabolic processes, hepatic protein, and glycogen synthesis, without inducing lipogenesis. These pathways can be disrupted in cholestasis, nonalcoholic fatty liver disease, and hepatocellular carcinoma. Thus, targeting FXR activity can represent a novel therapeutic approach for the prevention and the treatment of liver and metabolic diseases.

Keywords:  FGF15/19; FXR; agonist; bile acids; nonalcoholic fatty liver disease; nuclear receptors

DOI:  https://doi.org/10.3390/nu14234950
Am J Cancer Res. 2022 ;12(11): 5271-5285

Elevated bile acid metabolism and microbiome are associated with suppressed cell proliferation and better survival in breast cancer.

Rongrong Wu, Irene Yu, Yoshihisa Tokumaru, Mariko Asaoka, Masanori Oshi, Li Yan, Shujiro Okuda, Takashi Ishikawa, Kazuaki Takabe.

Bile acids are metabolized by the gut microbiome and are involved in fat absorption. Contrary to their carcinogenic role in gastrointestinal cancers, bile acids have been reported to inhibit cancer cell proliferation in breast cancer. The microbiome of breast cancer tissues may also influence cancer proliferation. We hypothesized that bile acid metabolism reflects its accumulation and is associated with certain microbiomes, breast cancer biology, and patient survival. Transcriptomic and clinicopathological information of a total of 6050 patients in three large open primary breast cancer cohorts (GSE96058, METABRIC, TCGA) and 16S rRNA gene sequence microbiome data of breast cancer tissues in TCGA were analyzed by high and low bile acid metabolism scores calculated by gene set variation analysis (GSVA). Breast cancers with high bile acid metabolism had a significantly improved survival across all three cohorts. Metabolic pathways related to the production and regulation of bile acids were consistently enriched in high bile acid metabolism groups across all cohorts. On the other hand, the low bile acid metabolism group was associated with higher Ki67 expression and Nottingham histological grade, as well as enrichment of cell proliferation-related gene sets. Intratumoral heterogeneity, homologous recombination deficiency, mutational load, activation of cancer immunity, and infiltration of anticancer immune cells were also higher in this group. Gammaretrovirus, Hymenobacter, Anaerococcus, and Collimonas were significantly more abundant in the high bile acid metabolism group compared to Lactobacillus, Ruegeria, and Marichromatium in the low metabolism group. Surprisingly, almost all Hallmark cell proliferation-associated gene sets were highly enriched in all three microorganisms that were abundant in the low bile acid metabolism group. In conclusion, microorganisms abundant in the breast tumor microenvironment with low bile acid metabolism are associated with aggressive cancer biology, including increased cell proliferation and poor survival.

Keywords: BRCA; Bile acid; GSVA; breast cancer; microbiome; tumor microenvironment
Brain Dev. 2023 Jan;pii: S0387-7604(22)00169-3. [Epub ahead of print]45(1): 58-69

Development of a system adapted for the diagnosis and evaluation of peroxisomal disorders by measuring bile acid intermediates.

Hiroki Kawai, Shigeo Takashima, Akiko Ohba, Kayoko Toyoshi, Kazuo Kubota, Hidenori Ohnishi, Nobuyuki Shimozawa.

   OBJECTIVE: Bile acid intermediates, 3α,7α,12α-trihydroxycholestanoic acid (THCA) and 3α,7α-dihydroxycholestanoic acid (DHCA), are metabolized in peroxisomes. Some peroxisomal disorders (PDs), such as Zellweger spectrum disorder (ZSD), show an accumulation of bile acid intermediates. In particular, ABCD3 deficiency and acyl-CoA-oxidase 2 deficiency are characterized by these metabolite abnormalities. In patients with ZSD, levels of bile acid intermediates can be lowered by a primary bile acid supplementation treatment; therefore, measuring their levels could help evaluate treatment effectiveness. Here, we established a method for the quantitative determination of bile acid intermediates (THCA/DHCA) for differentiating PDs and assessing bile acid treatment.
METHODS: Serum samples, obtained from patients with several forms of ZSD as well as peroxisomal β-oxidation enzyme deficiencies, were deproteinized and analyzed using liquid chromatography-mass spectrometry.
RESULTS: Levels of the bile acid intermediates increased significantly in patients with Zellweger syndrome (ZS) and slightly in patients with neonatal adrenoleukodystrophy and infantile Refsum disease (IRD), reflecting the severity of these diseases. One patient with ZS treated with primary bile acids for 6 months showed slightly decreased serum DHCA levels but significantly increased serum THCA levels. One patient with IRD who underwent living-donor liver transplantation showed a rapid decrease in serum THCA and DHCA levels, which remained undetected for 6 years. In all controls, THCA and DHCA levels were below the detection limit.
CONCLUSION: The analytical method developed in this study is useful for diagnosing various PD and validating bile acid treatment. Additionally, it can help predict the prognosis of patients with PD and support treatment strategies.

Keywords:  3α,7α,12α-Trihydroxycholestanoic acid (THCA); 3α,7α-Dihydroxycholestanoic acid (DHCA); Bile acid intermediate; Peroxisomal disorder

DOI:  https://doi.org/10.1016/j.braindev.2022.10.001
Int J Mol Sci. 2022 Nov 23. pii: 14607. [Epub ahead of print]23(23):

Recombinant Humanized IgG1 Antibody Promotes Reverse Cholesterol Transport through FcRn-ERK1/2-PPARα Pathway in Hepatocytes.

Zhonghao Li, Qi Zhang, Xianyan Liu, Ming Zhao.

  Hyperlipidemia-associated lipid disorders are considered the cause of atherosclerotic cardiovascular disease. Reverse cholesterol transport (RCT) is a mechanism by which excess peripheral cholesterol is transported to the liver and further converted into bile acid for excretion from the body in feces, which contributes to reducing hyperlipidemia as well as cardiovascular disease. We previously found that the recombinant humanized IgG1 antibody promotes macrophages to engulf lipids and increases cholesterol efflux to high-density lipoprotein (HDL) through ATP-binding cassette sub-family A1 (ABCA1), one of the key proteins related to RCT. In the present study, we explored other RCT related proteins expression on hepatocytes, including scavenger receptor class B type I (SR-BI), apolipoprotein A-I (ApoA-I), and apolipoprotein A-II (ApoA-II), and its modulation mechanism involved. We confirmed that the recombinant humanized IgG1 antibody selectively activated ERK1/2 to upregulate SR-BI, ApoA-I, and ApoA-II expression in mice liver and human hepatocellular carcinoma cell lines HepG2 cells. The rate-limiting enzymes of bile acid synthesis, including cholesterol 7α-hydroxylase (CYP7A1) and sterol 27-hydroxylase (CYP27A1), exhibited a significant increase when treated with the recombinant humanized IgG1 antibody, as well as increased excretion of bile acids in feces. Besides, abolishment or mutation of peroxisome proliferator-activated receptor α (PPARα)/RXR binding site on SR-BI promoter eliminated SR-BI reporter gene luciferase activity even in the presence of the recombinant humanized IgG1 antibody. Knock down the neonatal Fc receptor (FcRn) on hepatocytes impaired the effect of recombinant humanized IgG1 antibody on activation of ERK1/2, as well as upregulation of SR-BI, ApoA-I, and ApoA-II expression. In conclusion, one of the mechanisms on the recombinant humanized IgG1 antibody attenuates hyperlipidemia in ApoE-/- mice model fed with high-fat-diet might be through reinforcement of liver RCT function in an FcRn-ERK1/2-PPARα dependent manner.

Keywords:  hepatocytes; hyperlipidemia; recombinant humanized IgG1 antibody; reverse cholesterol transport

DOI:  https://doi.org/10.3390/ijms232314607
Cells. 2022 Nov 28. pii: 3810. [Epub ahead of print]11(23):

A High Hepatic Uptake of Conjugated Bile Acids Promotes Colorectal Cancer-Associated Liver Metastasis.

Zongmei Zheng, Jiao Wei, Xinxin Hou, Fengjing Jia, Zhaozhou Zhang, Haidong Guo, Fuwen Yuan, Feng He, Zunji Ke, Yan Wang, Ling Zhao.

  The liver is the most common site for colorectal cancer (CRC)-associated metastasis. There remain unsatisfactory medications in liver metastasis given the incomplete understanding of pathogenic mechanisms. Herein, with an orthotopic implantation model fed either regular or high-fat diets (HFD), more liver metastases were associated with an expansion of conjugated bile acids (BAs), particularly taurocholic acid (TCA) in the liver, and an increased gene expression of Na+-taurocholate cotransporting polypeptide (NTCP). Such hepatic BA change was more apparently shown in the HFD group. In the same model, TCA was proven to promote liver metastases and induce a tumor-favorable microenvironment in the liver, characterizing a high level of fibroblast activation and increased proportions of myeloid-derived immune cells. Hepatic stellate cells, a liver-residing source of fibroblasts, were dose-dependently activated by TCA, and their conditioned medium significantly enhanced the migration capability of CRC cells. Blocking hepatic BA uptake with NTCP neutralized antibody can effectively repress TCA-triggered liver metastases, with an evident suppression of tumor microenvironment niche formation. This study points to a new BA-driven mechanism of CRC-associated liver metastases, suggesting that a reduction of TCA overexposure by limiting liver uptake is a potential therapeutic option for CRC-associated liver metastasis.

Keywords:  Na+–taurocholate cotransporting polypeptide; bile acids; colorectal cancer—associated liver metastasis; high-fat diets

DOI:  https://doi.org/10.3390/cells11233810
Biomed Res. 2022 ;43(6): 223-239

Secondary bile acid lithocholic acid attenuates neurally evoked ion transport in the rat distal colon.

Kohei Takahashi, Yuko Kuwahara, Ikuo Kato, Shinji Asano, Takaharu Kozakai, Yoshinori Marunaka, Atsukazu Kuwahara.

The inhibitory action of the secondary bile acid lithocholic acid (LCA) on neurally evoked Cl-/HCO3- secretion was investigated using the Ussing-chambered mucosal-submucosal preparation from the rat distal colon. Electrical field stimulation (EFS) evoked cholinergic and noncholinergic secretory responses in the rat distal colon. The responses were almost completely blocked by TTX (10-6 M) but not atropine (10-5 M) or hexamethonium (10-4 M). The selective antagonist for VIP receptor 1 (VPAC1) greatly reduced the EFS-evoked response. Thus, the rat distal colon may be predominantly innervated by noncholinergic VIP secretomotor neurons. Basolateral addition of 6 × 10-5 M LCA inhibited the EFS-evoked response. The inhibitory action of LCA was partly rescued by the Y2R antagonist BIIE0246. The bile acid receptor TGR5 agonist INT-777 mimicked the LCA-induced inhibitory action. Immunohistochemical staining showed the colocalization of TGR5 and PYY on L cells. TGR5 immunoreactivity was also found in VIP-immunoreactive submucosal neurons which also expressed the PYY receptor, Y2R. These results suggest that LCA inhibits neurally evoked Cl-/HCO3- secretion through the activation of TGR5 on L cells and cholinergic- and VIP-secretomotor neurons in the submucosal plexus. Furthermore, the inhibitory mechanism may involve TGR5-stimulated PYY release from L cells and Y2R activation in VIP-secretomotor neurons.

DOI: https://doi.org/10.2220/biomedres.43.223