bims-liverm 2022-11-27 papers

bims-liverm

Biomed News

on Liver Metabolism

Issue of 2022–11–27
eleven papers selected by

Novel Nitroxide-Bile Acid Conjugates Inform Substrate Requirements for Human Bile Acid Transporters.
Bile Acids: Physiological Activity and Perspectives of Using in Clinical and Laboratory Diagnostics.
Bile acids as carcinogens in the colon and at other sites in the gastrointestinal system.
The function of xenobiotics receptors in metabolic diseases.
Loss of Apical Sodium Bile Acid Transporter Disrupts Bile Acid Circulation and Reduces Biliary Damage in Cholangitis.
Mechanisms and Outcomes of Metabolic Surgery in Type 2 Diabetes.
Liver Steatosis and Steatohepatitis Alter Bile Acid Receptors in Brain and Induce Neuroinflammation: A Contribution of Circulating Bile Acids and Blood-Brain Barrier.
High Levels of Serum Bile Acids in COVID-19 Patients on Hospital Admission.
Is TGR5 a therapeutic target for the treatment of spinal cord injury?
Role of bile acid receptor FXR in development and function of brown adipose tissue.
HGFAC is a ChREBP regulated hepatokine that enhances glucose and lipid homeostasis.

Eur J Pharm Sci. 2022 Nov 16. pii: S0928-0987(22)00220-2. [Epub ahead of print] 106335

Novel Nitroxide-Bile Acid Conjugates Inform Substrate Requirements for Human Bile Acid Transporters.

Melissa Metry, Nathaniel D A Dirda, Jean-Pierre Raufman, James E Polli, Joseph P Y Kao.

  Transport of bile acids within the enterohepatic circulation from the liver to the intestines via the gallbladder and back to the liver via the portal vein plays a critical role in bile acid regulation and homeostasis. Deficiency of fibroblast growth factor 19 (FGF19), a hormone whose role is to suppress de novo hepatic bile acid synthesis to maintain homeostatic levels, results in bile acid diarrhea (BAD). FGF19 also modulates gallbladder motility so that bile acids are concentrated in the gallbladder until postprandial contraction. To assess bile acid transport and diagnose ailments like BAD that are associated with altered bile acid synthesis and transport, we created bile acid conjugates with nitroxide radicals. Because nitroxides are paramagnetic and can promote proton relaxation, we reasoned that these paramagnetic conjugates should act as contrast agents in in vivo magnetic resonance imaging (MRI). We tested substrate capability by assessing the inhibitory potential of these novel agents against taurocholate uptake by the apical sodium dependent bile acid transporter (ASBT) and the Na+/taurocholate cotransporting polypeptide (NTCP). Surprisingly, neither the paramagnetic compounds CA-Px-1 and CA-Px-2, nor their reduced forms, CA-Px-1H and CA-Px-2H, inhibited hASBT- or hNTCP-mediated taurocholate uptake. Therefore, the new conjugates cannot serve as contrast agents for MRI in vivo. However, our findings identify important structural constraints of transportable bile acid conjugates and suggest potential modifications to overcome these limitations.

Keywords:  Bile acids; enterohepatic circulation; nitroxides; transporters

DOI:  https://doi.org/10.1016/j.ejps.2022.106335
Molecules. 2022 Nov 13. pii: 7830. [Epub ahead of print]27(22):

Bile Acids: Physiological Activity and Perspectives of Using in Clinical and Laboratory Diagnostics.

Yaroslav Shansky, Julia Bespyatykh.

  Bile acids play a significant role in the digestion of nutrients. In addition, bile acids perform a signaling function through their blood-circulating fraction. They regulate the activity of nuclear and membrane receptors, located in many tissues. The gut microbiota is an important factor influencing the effects of bile acids via enzymatic modification. Depending on the rate of healthy and pathogenic microbiota, a number of bile acids may support lipid and glucose homeostasis as well as shift to more toxic compounds participating in many pathological conditions. Thus, bile acids can be possible biomarkers of human pathology. However, the chemical structure of bile acids is similar and their analysis requires sensitive and specific methods of analysis. In this review, we provide information on the chemical structure and the biosynthesis of bile acids, their regulation, and their physiological role. In addition, the review describes the involvement of bile acids in various diseases of the digestive system, the approaches and challenges in the analysis of bile acids, and the prospects of their use in omics technologies.

Keywords:  bile acids metabolism; high-performance liquid chromatography; mass spectrometry; metabolome

DOI:  https://doi.org/10.3390/molecules27227830
Exp Biol Med (Maywood). 2022 Nov 19. 15353702221131858

Bile acids as carcinogens in the colon and at other sites in the gastrointestinal system.

Harris Bernstein, Carol Bernstein.

  Colon cancer incidence is associated with a high-fat diet. Such a diet is linked to elevated levels of bile acids in the gastrointestinal system and the circulation. Secondary bile acids are produced by microorganisms present at high concentrations in the colon. Recent prospective studies and a retrospective study in humans associate high circulating blood levels of secondary bile acids with increased risk of colon cancer. Feeding mice a diet containing a secondary bile acid, so their feces have the bile acid at a level comparable to that in the feces of humans on a high-fat diet, also causes colon cancer in the mice. Studies using human cells grown in culture illuminate some mechanisms by which bile acids cause cancer. In human cells, bile acids cause oxidative stress leading to oxidative DNA damage. Increased DNA damage increases the occurrence of mutations and epimutations, some of which provide a cellular growth advantage such as apoptosis resistance. Cells with such mutations/epimutations increase by natural selection. Apoptosis, or programmed cell death, is a beneficial process that eliminates cells with unrepaired DNA damage, whereas apoptosis-resistant cells are able to survive DNA damage using inaccurate repair processes. This results in apoptosis-resistant cells having more frequent mutations/epimutations, some of which are carcinogenic. The experiments on cultured human cells have provided a basis for understanding at the molecular level the human studies that recently reported an association of bile acids with colon cancer, and the mouse studies showing directly that bile acids cause colon cancer. Similar, but more limited, findings of an association of dietary bile acids with other cancers of the gastrointestinal system suggest that understanding the role of bile acids in colon carcinogenesis may contribute to understanding carcinogenesis in other organs.

Keywords:  Carcinogenesis; DNA damage; apoptosis; gastrointestinal cancer; oxidative stress

DOI:  https://doi.org/10.1177/15353702221131858
Drug Metab Dispos. 2022 Nov 22. pii: DMD-AR-2022-000862. [Epub ahead of print]

The function of xenobiotics receptors in metabolic diseases.

Jinhang Zhang, Qingyi Jia, Yanping Li, Jinhan He.

  Metabolic diseases are a series of metabolic disorders that include obesity, diabetes, insulin resistance, hypertension, and hyperlipidemia. The increased prevalence of metabolic diseases has resulted in higher mortality and mobility rates over the past decades, and this has led to extensive research focusing on the underlying mechanisms. Xenobiotic receptors (XRs) are a series of xenobiotic-sensing nuclear receptors that regulate their downstream target genes expression, thus defending the body from xenobiotic and endotoxin attacks. XR activation is associated with the development of a number of metabolic diseases such as obesity, nonalcoholic fatty liver disease (NAFLD), type 2 diabetes (T2D), and cardiovascular diseases, thus suggesting an important role for XRs in modulating metabolic diseases. However, the regulatory mechanism of XRs in the context of metabolic disorders under different nutrient conditions is complex and remains controversial. This review summarizes the effects of XRs on different metabolic components (cholesterol, lipids, glucose, and bile acids) in different tissues during metabolic diseases. As chronic inflammation plays a critical role in the initiation and progression of metabolic diseases, we also discuss the impact of XRs on inflammation to comprehensively recognize the role of XRs in metabolic diseases. This will provide new ideas for treating metabolic diseases by targeting XRs. Significance Statement This review outlines the current understanding of xenobiotic receptors on nutrient metabolism and inflammation during metabolic diseases. This work also highlights the gaps in this field, which can be used to direct the future investigations on metabolic diseases treatment by targeting xenobiotic receptors.

Keywords:  Receptor down-regulation; inflammation

DOI:  https://doi.org/10.1124/dmd.122.000862
Am J Physiol Gastrointest Liver Physiol. 2022 Nov 21.

Loss of Apical Sodium Bile Acid Transporter Disrupts Bile Acid Circulation and Reduces Biliary Damage in Cholangitis.

Vik Meadows, Corinn Marakovits, Burcin Ekser, Debjyoti Kundu, Tianhao Zhou, Konstantina Kyritsi, Linh Pham, Lixian Chen, Lindsey Kennedy, Ludovica Ceci, Nan Wu, Guido Carpino, Wenjun Zhang, Abdulkadir Isidan, Alison Meyer, Travis Owen, Eugenio Gaudio, Paolo Onori, Gianfranco D Alpini, Heather Francis.

   BACKGROUND: Primary Sclerosing Cholangitis (PSC) is characterized by increased ductular reaction (DR), liver fibrosis, hepatic total bile acid (TBA) levels, and mast cell (MC) infiltration. Apical sodium BA transporter (ASBT) expression increases in cholestasis, and ileal inhibition reduces PSC phenotypes.
METHODS: FVB/NJ and Mdr2-/- mice were treated with control or ASBT Vivo-Morpholino. We measured (i) ASBT expression and MC presence in liver/ileum; (ii) liver damage/DR; (iii) hepatic fibrosis/inflammation; (iv) biliary inflammation/histamine serum content; and (v) intestinal permeability/hepatic bacterial translocation. TBA/BA composition was measured in cholangiocyte/hepatocyte supernatants, intestine, liver, serum, and feces. Shotgun analysis was performed to ascertain microbiome changes. In vitro, cholangiocytes were treated with BAs +/- ASBT Vivo-Morpholino and histamine content and FXR signaling were determined. Treated cholangiocytes were co-cultured with MCs, and FXR signaling, inflammation, and MC activation measured. Human patients were evaluated for ASBT/MC expression and histamine/TBA content in bile. Control patient- and PSC patient-derived 3D organoids were generated; ASBT, chymase, histamine, and fibroblast growth factor-19 (FGF19) were evaluated.
RESULTS: ASBT Vivo-Morpholino in Mdr2-/- mice decreased (i) biliary ASBT expression; (ii) PSC phenotypes; (iii) hepatic TBA; and (iv) intestinal permeability compared to control. We found alterations between WT and Mdr2-/- mice microbiome and ASBT/MC and bile histamine content increased in cholestatic patients. BA-stimulated cholangiocytes increased MC activation/FXR signaling via ASBT, and human PSC-derived 3D organoids secrete histamine/FGF19.
CONCLUSION: Inhibition of hepatic ASBT ameliorates cholestatic phenotypes by reducing cholehepatic BA signaling, biliary inflammation and histamine levels. ASBT regulation of hepatic BA signaling offers a therapeutic avenue for PSC.

Keywords:  Gut/liver axis; PSC; bile acids; cholehepatic shunt; mast cells

DOI:  https://doi.org/10.1152/ajpgi.00112.2022
Metabolites. 2022 Nov 17. pii: 1134. [Epub ahead of print]12(11):

Mechanisms and Outcomes of Metabolic Surgery in Type 2 Diabetes.

Mansor Fazliana, Zubaidah Nor Hanipah.

  This review is aimed at synthesizing the mechanisms and outcomes of metabolic surgery on the endocrine system, microbiome, metabolomics, and at the molecular level. We review the hormonal, adipokine, microbiota, microRNA, and metabolomic changes in human and animal models following metabolic surgery for the treatment of obesity and diabetes. The most relevant studies in this area over the past 17 years have been considered for this review. In most cases, metabolic procedures, especially those that include intestinal bypass components, showed the remission of type 2 diabetes. This involves a variety of weight-independent mechanisms to improve glucose homeostasis, improving insulin sensitivity and secretion, gut microbiota, and bile acid cross-talk.

Keywords:  bariatric surgery; diabetes; endocrine; gut microbiota; metabolic surgery; metabolomics; microRNA

DOI:  https://doi.org/10.3390/metabo12111134
Int J Mol Sci. 2022 Nov 17. pii: 14254. [Epub ahead of print]23(22):

Liver Steatosis and Steatohepatitis Alter Bile Acid Receptors in Brain and Induce Neuroinflammation: A Contribution of Circulating Bile Acids and Blood-Brain Barrier.

Noemi Fiaschini, Mariateresa Mancuso, Mirella Tanori, Eleonora Colantoni, Roberta Vitali, Gianfranco Diretto, Laura Lorenzo Rebenaque, Laura Stronati, Anna Negroni.

  A tight relationship between gut-liver diseases and brain functions has recently emerged. Bile acid (BA) receptors, bacterial-derived molecules and the blood-brain barrier (BBB) play key roles in this association. This study was aimed to evaluate how non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) impact the BA receptors Farnesoid X receptor (FXR) and Takeda G-protein coupled receptor 5 (TGR5) expression in the brain and to correlate these effects with circulating BAs composition, BBB integrity and neuroinflammation. A mouse model of NAFLD was set up by a high-fat and sugar diet, and NASH was induced with the supplementation of dextran-sulfate-sodium (DSS) in drinking water. FXR, TGR5 and ionized calcium-binding adaptor molecule 1 (Iba-1) expression in the brain was detected by immunohistochemistry, while Zonula occludens (ZO)-1, Occludin and Plasmalemmal Vesicle Associated Protein-1 (PV-1) were analyzed by immunofluorescence. Biochemical analyses investigated serum BA composition, lipopolysaccharide-binding protein (LBP) and S100β protein (S100β) levels. Results showed a down-regulation of FXR in NASH and an up-regulation of TGR5 and Iba-1 in the cortex and hippocampus in both treated groups as compared to the control group. The BA composition was altered in the serum of both treated groups, and LBP and S100β were significantly augmented in NASH. ZO-1 and Occludin were attenuated in the brain capillary endothelial cells of both treated groups versus the control group. We demonstrated that NAFLD and NASH provoke different grades of brain dysfunction, which are characterized by the altered expression of BA receptors, FXR and TGR5, and activation of microglia. These effects are somewhat promoted by a modification of circulating BAs composition and by an increase in LBP that concur to damage BBB, thus favoring neuroinflammation.

Keywords:  bile acid receptors; bile acids; blood brain barrier; brain inflammation; high-fat diet; intestinal inflammation; liver

DOI:  https://doi.org/10.3390/ijms232214254
MEDICC Rev. 2022 Oct 31. 24(3-4): 53-56

High Levels of Serum Bile Acids in COVID-19 Patients on Hospital Admission.

Felipe N Piñol-Jiménez, Virginia Capó-de Paz, Julián F Ruiz-Torres, Teresita Montero-González, Sara A Urgellés-Carreras, Andrés Breto-García, Armando Amador-Armenteros, María M Llerena-Mesa, Ana G Galarraga-Lazcano.

   INTRODUCTION: Bile acids are signaling molecules with immune, metabolic and intestinal microbiota control actions. In high serum concentrations they increase inflammatory response from the liver-gut axis, until causing multiorgan failure and death; therefore, they may be associated with COVID-19's clinical progression, as a consequence of tissue and metabolic damage caused by SARS-CoV-2. While this topic is of considerable clinical interest, to our knowledge, it has not been studied in Cuba.
OBJECTIVE: Study and preliminarily characterize patients admitted with a diagnosis of COVID-19 and high levels of serum bile acids.
METHODS: A preliminary exploratory study was carried out with descriptive statistical techniques in 28 COVID-19 patients (17 women, 11 men; aged 19-92 years) who exhibited high levels of serum bile acids (≥10.1 µmol/L) on admission to the Dr. Luis Díaz Soto Central Military Hospital in Havana, Cuba, from September through November 2021.
RESULTS: On admission patients presented hypocholesterolemia (13/28; 46.4%), hyperglycemia (12/28; 43.0%) and hyper gamma-glutamyl transpeptidase (23/28; 84.2%). Median blood glucose (5.8 mmol/L) and cholesterol (4.1 mmol/L) were within normal ranges (3.2‒6.2 mmol/L and 3.9‒5.2 mmol/L, respectively). Severe or critical stage was the most frequent (13/28) and median serum bile acids (31.6 µmol/L) and gamma-glutamyl transferase (108.6 U/L) averaged well above their respective normal ranges (serum bile acids: 0‒10 µmol/L; GGT: 9‒36 U/L). Arterial hypertension was the most frequent comorbidity (19/28; 67.9%).
CONCLUSIONS: Severe or critical stage predominated, with serum bile acids and gamma-glutamyl transferase blood levels above normal ranges. The study suggests that serum bile acid is toxic at levels ≥10.1 µmol/L, and at such levels is involved in the inflammatory process and in progression to severe and critical clinical stages of the disease. In turn, this indicates the importance of monitoring bile acid homeostasis in hospitalized COVID-19 patients and including control of its toxicity in treatment protocols.

Keywords:  COVID-19; Cuba; SARS-CoV-2; bile acids and salts; gamma-glutamyl transferase; postpartum; pregnant women

DOI:  https://doi.org/10.37757/mr2022.v24.n3-4.8
J Neurochem. 2022 Nov 21.

Is TGR5 a therapeutic target for the treatment of spinal cord injury?

Anna Smaling, Lorenzo Romero-Ramírez, Jörg Mey.

  Bile acids, which are synthesized in liver and colon, facilitate the digestion of dietary lipids. In addition to this metabolic function, they also act as molecular signals with activities in the nervous system. These are mediated primarily by a G protein-coupled bile acid receptor (known as TGR5). Preceded by a long tradition in Chinese medicine, bile acids are now being investigated as therapeutic options in several neuropathologies. Specifically, one bile acid, tauroursodeoxycholic acid (TUDCA), which passes the blood-brain barrier and shows anti-inflammatory and anti-apoptotic effects, has been tested in animal models of spinal cord injury (SCI). In this review we discuss the evidence for a therapeutic benefit in these preclinical experiments. At the time of writing, twelve studies with TGR5 agonists have been published that report functional outcomes with rodent models of SCI. Most investigations found cytoprotective effects and benefits regarding the recovery of sensorimotor function in the subacute phase. When TUDCA was applied in a hydrogel into the lesion site, a significant improvement was obtained at two weeks after SCI. However, no lasting improvements with TUDCA treatment were found, when animals were assessed in later, chronic stages. A combination of TUDCA with stem cell injection failed to improve the effect of the cellular treatment. We conclude that the evidence does not support the use of TUDCA as a treatment of SCI. Nevertheless, cytoprotective effects suggest that different modes of application or combinatorial therapies might still be explored.

Keywords:  Spinal cord injury; TGR5; apoptosis; bile acid; inflammation

DOI:  https://doi.org/10.1111/jnc.15727
Biochim Biophys Acta Mol Cell Biol Lipids. 2022 Nov 16. pii: S1388-1981(22)00147-0. [Epub ahead of print] 159257

Role of bile acid receptor FXR in development and function of brown adipose tissue.

J Yang, H D de Vries, A Mayeuf-Louchart, J H Stroeve, V W Bloks, M Koehorst, H Duez, B Staels, F Kuipers, T van Zutphen.

  Bile acids act as signalling molecules that contribute to maintenance of energy homeostasis in mice and humans. Activation of G-protein-coupled bile acid receptor TGR5 induces energy expenditure in brown adipose tissue (BAT). However, a role for the nuclear bile acid receptor Farnesoid X receptor (FXR) in BAT has remained ambiguous. We aimed to study the potential role of FXR in BAT development and functioning. Here we demonstrate low yet detectable expression of the α1/2 isoforms of FXR in murine BAT that markedly decreases upon cold exposure. Moderate adipose tissue-specific FXR overexpression in mice induces pronounced BAT whitening, presenting with large intracellular lipid droplets and extracellular collagen deposition. Expression of thermogenic marker genes including the target of Tgr5, Dio2, was significantly lower in BAT of chow-fed aP2-hFXR mice compared to wild-type controls. Transcriptomic analysis revealed marked up-regulation of extracellular matrix formation and down-regulation of mitochondrial functions in BAT from aP2-hFXR mice. In addition, markers of cell type lineages deriving from the dermomyotome, such as myocytes, as well as markers of cellular senescence were strongly induced. The response to cold and β3-adrenergic receptor agonism was blunted in these mice, yet resolved BAT whitening. Newborn cholestatic Cyp2c70-/- mice with a human-like bile acid profile also showed distinct BAT whitening and upregulation of myocyte-specific genes, while thermogenic markers were down-regulated. Ucp1 expression inversely correlated with plasma bile acid levels. Therefore, bile acid signalling via FXR has a role in BAT function already early in tissue development. Functionally, FXR activation appears to oppose TGR5-mediated thermogenesis.

Keywords:  Bile acids; Brown adipose tissue; Cold exposure; Extracellular matrix; FXR; β3-Adrenergic receptor agonist

DOI:  https://doi.org/10.1016/j.bbalip.2022.159257
JCI Insight. 2022 Nov 22. pii: e153740. [Epub ahead of print]

HGFAC is a ChREBP regulated hepatokine that enhances glucose and lipid homeostasis.

Ashot Sargsyan, Ludivine Doridot, Sarah Anissa Hannou, Wenxin Tong, Harini Srinivasan, Rachael Ivison, Ruby Monn, Henry H Kou, Jonathan M Haldeman, Michelle Arlotto, Phillip J White, Paul A Grimsrud, Inna Astapova, Linus T-Y Tsai, Mark A Herman.

  Carbohydrate Responsive Element-Binding Protein (ChREBP) is a carbohydrate sensing transcription factor that regulates both adaptive and maladaptive genomic responses in coordination of systemic fuel homeostasis. Genetic variants in the ChREBP locus associate with diverse metabolic traits in humans, including circulating lipids. To identify novel ChREBP-regulated hepatokines that contribute to its systemic metabolic effects, we integrated ChREBP ChIP-seq analysis in mouse liver with human genetic and genomic data for lipid traits and identified Hepatocyte Growth Factor Activator (HGFAC) as a promising ChREBP-regulated candidate in mice and humans. HGFAC is a protease that activates the pleiotropic hormone Hepatocyte Growth Factor (HGF). We demonstrate that HGFAC KO mice have phenotypes concordant with putative loss-of-function variants in human HGFAC. Moreover, in gain- and loss-of-function genetic mouse models, we demonstrate that HGFAC enhances lipid and glucose homeostasis, which may be mediated in part through actions to activate hepatic PPARγ activity. Together, our studies show that ChREBP mediates an adaptive response to overnutrition via activation of HGFAC in the liver to preserve glucose and lipid homeostasis.

Keywords:  Carbohydrate metabolism; Glucose metabolism; Growth factors; Metabolism

DOI:  https://doi.org/10.1172/jci.insight.153740