bims-liverm 2023-02-12 papers

bims-liverm

Biomed News

on Liver Metabolism

Issue of 2023–02–12
nine papers selected by

The Black Box Orchestra of Gut Bacteria and Bile Acids: Who Is the Conductor?
Bile acids as modulators of gut microbiota composition and function.
Novel mutation in the HSD3B7 gene causes bile acid synthetic disorder and presents as recurrent liver failure in early childhood.
Fructose drives de novo lipogenesis affecting metabolic health.
Semi-Targeted Profiling of Bile Acids by High-Resolution Mass Spectrometry in a Rat Model of Drug-Induced Liver Injury.
Emerging Links between Nonalcoholic Fatty Liver Disease and Neurodegeneration.
Adipose-targeted SWELL1 deletion exacerbates obesity and age-related non-alcoholic fatty liver disease.
SLC46A3 is a lysosomal proton-coupled steroid conjugate and bile acid transporter involved in transport of active catabolites of T-DM1.
Adipocyte-specific FXR-deficiency protects adipose tissue from oxidative stress and insulin resistance and improves glucose homeostasis.

Int J Mol Sci. 2023 Jan 17. pii: 1816. [Epub ahead of print]24(3):

The Black Box Orchestra of Gut Bacteria and Bile Acids: Who Is the Conductor?

Soumia Majait, Max Nieuwdorp, Marleen Kemper, Maarten Soeters.

  Over the past decades the potential role of the gut microbiome and bile acids in type 2 diabetes mellitus (T2DM) has been revealed, with a special reference to low bacterial alpha diversity. Certain bile acid effects on gut bacteria concern cytotoxicity, or in the case of the microbiome, bacteriotoxicity. Reciprocally, the gut microbiome plays a key role in regulating the bile acid pool by influencing the conversion and (de)conjugation of primary bile acids into secondary bile acids. Three main groups of bacterial enzymes responsible for the conversion of bile acids are bile salt hydrolases (BSHs), hydroxysteroid dehydrogenases (HSDHs) and enzymes encoded in the bile acid inducible (Bai) operon genes. Interventions such as probiotics, antibiotics and fecal microbiome transplantation can impact bile acids levels. Further evidence of the reciprocal interaction between gut microbiota and bile acids comes from a multitude of nutritional interventions including macronutrients, fibers, prebiotics, specific individual products or diets. Finally, anatomical changes after bariatric surgery are important because of their metabolic effects. The heterogeneity of studies, diseases, bacterial species and (epi)genetic influences such as nutrition may challenge establishing specific and detailed interventions that aim to tackle the gut microbiome and bile acids.

Keywords:  bile acids; enterohepatic circulation; gut microbiome; nutrition; prebiotics; probiotics; type 2 diabetes mellitus

DOI:  https://doi.org/10.3390/ijms24031816
Gut Microbes. 2023 Jan-Dec;15(1):15(1): 2172671

Bile acids as modulators of gut microbiota composition and function.

Anaïs B Larabi, Hugo L P Masson, Andreas J Bäumler.

  Changes in the composition of gut-associated microbial communities are associated with many human illnesses, but the factors driving dysbiosis remain incompletely understood. One factor governing the microbiota composition in the gut is bile. Bile acids shape the microbiota composition through their antimicrobial activity and by activating host signaling pathways that maintain gut homeostasis. Although bile acids are host-derived, their functions are integrally linked to bacterial metabolism, which shapes the composition of the intestinal bile acid pool. Conditions that change the size or composition of the bile acid pool can trigger alterations in the microbiota composition that exacerbate inflammation or favor infection with opportunistic pathogens. Therefore, manipulating the composition or size of the bile acid pool might be a promising strategy to remediate dysbiosis.

Keywords:  Bile acids; colonization resistance; intestinal homeostasis; microbiome

DOI:  https://doi.org/10.1080/19490976.2023.2172671
BMJ Case Rep. 2023 Feb 07. pii: e245852. [Epub ahead of print]16(2):

Novel mutation in the HSD3B7 gene causes bile acid synthetic disorder and presents as recurrent liver failure in early childhood.

Yaja Jebaying, Karunesh Kumar, Smita Malhotra, Anupam Sibal.

  Bile acid synthetic disorders are rare inborn errors of metabolism, and presentations include neonatal cholestasis, neurological disease or deficiency of fat-soluble vitamins. Affected patients fail to produce standard bile acids but accumulate unusual bile acids and intermediates, resulting in liver failure and complications. Most of them improve with bile acid supplementation, but delaying initiating treatment is detrimental to the outcome.A young child presented to us with recurrent episodes of acute liver failure. In the first episode, both coagulopathy and encephalopathy improved on supportive treatment, but the aetiological evaluation was inconclusive. During the second presentation, whole-exome sequencing was sent, identifying a compound heterozygous novel mutation in the 3-β-hydroxysteroid dehydrogenase type 7 gene leading to bile acid synthetic defect.

Keywords:  Bilirubin disorders; Genetics; Liver disease

DOI:  https://doi.org/10.1136/bcr-2021-245852
J Endocrinol. 2023 Feb 01. pii: JOE-22-0270. [Epub ahead of print]

Fructose drives de novo lipogenesis affecting metabolic health.

Bettina Geidl-Flueck, Philipp A Gerber.

Despite the existence of numerous studies supporting a pathological link between fructose consumption and the development of the metabolic syndrome and its sequelae, such as non-alcoholic fatty liver disease (NAFLD), this link remains a contentious issue. With this article, we shed a light on the impact of sugar/fructose intake on hepatic de novo lipogenesis (DNL), an outcome parameter known to be dysregulated in subjects with type 2 diabetes and/or NAFLD. In this review, we present findings from human intervention studies using physiological doses of sugar as well as mechanistic animal studies. There is evidence from both human and animal studies that fructose is a more potent inducer of hepatic lipogenesis than glucose. This is most likely due to the liver's prominent physiological role in fructose metabolism, which may be disrupted under pathological conditions by increased hepatic expression of fructolytic and lipogenic enzymes. Increased DNL may not only contribute to ectopic fat deposition (i.e., in the liver), but it may also impair several metabolic processes through DNL-related fatty acids (e.g., beta-cell function, insulin secretion, or insulin sensitivity).

DOI: https://doi.org/10.1530/JOE-22-0270
Int J Mol Sci. 2023 Jan 27. pii: 2489. [Epub ahead of print]24(3):

Semi-Targeted Profiling of Bile Acids by High-Resolution Mass Spectrometry in a Rat Model of Drug-Induced Liver Injury.

Myriam Mireault, Vivaldy Prinville, Leanne Ohlund, Lekha Sleno.

  Using a semi-targeted approach, we have investigated the effect of acetaminophen on circulating bile acid profiles in rats, including many known bile acids and potential isomeric structures, as well as glucuronide and sulfate conjugates. The chromatographic separation was based on an optimized reverse-phase method exhibiting excellent resolution for a complex mix of bile acids using a solid-core C18 column, coupled to a high-resolution quadrupole time-of-flight system. The semi-targeted workflow consisted of first assigning all peaks detectable in samples from 46 known bile acids contained in a standard mix, as well as additional peaks for other bile acid isomers. The presence of glucuronide and sulfate conjugates was also examined based on their elemental formulae and detectable peaks with matching exact masses were added to the list of features for statistical analysis. In this study, rats were administered acetaminophen at four different doses, from 75 to 600 mg/kg, with the highest dose being a good model of drug-induced liver injury. Statistically significant changes were found by comparing bile acid profiles between dosing levels. Some tentatively assigned conjugates were further elucidated using in vitro metabolism incubations with rat liver fractions and standard bile acids. Overall, 13 identified bile acids, 23 tentatively assigned bile acid isomers, and 9 sulfate conjugates were found to increase significantly at the highest acetaminophen dose, and thus could be linked to drug-induced liver injury.

Keywords:  acetaminophen; bile acids; drug-induced liver injury; hepatotoxicity; liquid chromatography–high resolution mass spectrometry; metabolomics; rat plasma

DOI:  https://doi.org/10.3390/ijms24032489
Semin Liver Dis. 2023 Feb 10.

Emerging Links between Nonalcoholic Fatty Liver Disease and Neurodegeneration.

Taylor J Kelty, Ryan J Dashek, W David Arnold, R Scott Rector.

The association between liver and brain health has gained attention as biomarkers of liver function have been revealed to predict neurodegeneration. The liver is a central regulator in metabolic homeostasis. However, in nonalcoholic fatty liver disease (NAFLD), homeostasis is disrupted which can result in extrahepatic organ pathologies. Emerging literature provides insight into the mechanisms behind the liver-brain health axis. These include the increased production of liver-derived factors that promote insulin resistance and loss of neuroprotective factors under conditions of NAFLD that increase insulin resistance in the central nervous system. In addition, elevated proinflammatory cytokines linked to NAFLD negatively impact the blood-brain barrier and increase neuroinflammation. Furthermore, exacerbated dyslipidemia associated with NAFLD and hepatic dysfunction can promote altered brain bioenergetics and oxidative stress. In this review, we summarize the current knowledge of the crosstalk between liver and brain as it relates to the pathophysiology between NAFLD and neurodegeneration, with an emphasis on Alzheimer's disease. We also highlight knowledge gaps and future areas for investigation to strengthen the potential link between NAFLD and neurodegeneration.

DOI: https://doi.org/10.1055/s-0043-1762585
JCI Insight. 2023 Feb 07. pii: e154940. [Epub ahead of print]

Adipose-targeted SWELL1 deletion exacerbates obesity and age-related non-alcoholic fatty liver disease.

Susheel K Gunasekar, John Heebink, Danielle H Carpenter, Ashutosh Kumar, Litao Xie, Haixia Zhang, Joel D Schilling, Rajan Sah.

  Healthy expansion of adipose tissue is critical for the maintenance of metabolic health - providing an optimized reservoir for energy storage in the form of triacylglycerol-rich lipoproteins. Dysfunctional adipocytes that are unable to efficiently store lipid can result in lipodystrophy and contribute to nonalcoholic fatty liver disease (NAFLD) and metabolic syndrome. LRRC8a/SWELL1 functionally encodes the volume-regulated anion channel (VRAC) complex in adipocytes, is induced in early obesity, and required for normal adipocyte expansion during high-fat feeding. Adipose-specific SWELL1 ablation (Adipo KO) leads to insulin resistance and hyperglycemia during caloric excess, both of which are associated with NAFLD. Here, we show that Adipo KO mice exhibit impaired adipose depot expansion and excess lipolysis when raised on a variety of high-fat diets, resulting in increased diacylglycerides and hepatic steatosis thereby driving liver injury. Liver lipidomic analysis revealed increases in oleic acid containing hepatic triacylglycerides and injurious hepatic diacylglyceride species, with reductions in hepatocyte protective phospholipids, and anti-inflammatory free fatty acids. Aged Adipo KO mice develop hepatic steatosis on a regular chow diet, and Adipo KO male mice develop spontaneous, aggressive hepatocellular carcinomas (HCC). These data highlight the importance of adipocyte SWELL1 for healthy adipocyte expansion to protect against NAFLD and HCC in the setting of over nutrition and with aging.

Keywords:  Adipose tissue; Glucose metabolism; Hepatology; Liver cancer; Metabolism

DOI:  https://doi.org/10.1172/jci.insight.154940
PNAS Nexus. 2022 Jul;1(3): pgac063

SLC46A3 is a lysosomal proton-coupled steroid conjugate and bile acid transporter involved in transport of active catabolites of T-DM1.

Ryuto Tomabechi, Hisanao Kishimoto, Taeka Sato, Naoki Saito, Keisuke Kiyomiya, Tappei Takada, Kei Higuchi, Yoshiyuki Shirasaka, Katsuhisa Inoue.

  Antibody-drug conjugates (ADCs) represent a new class of cancer therapeutics that enable targeted delivery of cytotoxic drugs to cancer cells. Although clinical efficacy has been demonstrated for ADC therapies, resistance to these conjugates may occur. Recently, SLC46A3, a lysosomal membrane protein, was revealed to regulate the efficacy of trastuzumab emtansine (T-DM1), a noncleavable ADC that has been widely used for treating breast cancer. However, the role of SLC46A3 in mediating T-DM1 cytotoxicity remains unclear. In this study, we discovered the function of SLC46A3 as a novel proton-coupled steroid conjugate and bile acid transporter. SLC46A3 preferentially recognized lipophilic steroid conjugates and bile acids as endogenous substrates. In addition, we found that SLC46A3 directly transports Lys-SMCC-DM1, a major catabolite of T-DM1, and potent SLC46A3 inhibitors attenuate the cytotoxic effects of T-DM1, suggesting a role in the escape of Lys-SMCC-DM1 from the lysosome into the cytoplasm. Our findings reveal the molecular mechanism by which T-DM1 kills cancer cells and may contribute to the rational development of ADCs that target SLC46A3.

Keywords:  SLC46A3; and trastuzumab emtansine; antibody–drug conjugate; bile acid; steroid conjugate

DOI:  https://doi.org/10.1093/pnasnexus/pgac063
Mol Metab. 2023 Feb 04. pii: S2212-8778(23)00020-0. [Epub ahead of print] 101686

Adipocyte-specific FXR-deficiency protects adipose tissue from oxidative stress and insulin resistance and improves glucose homeostasis.

Hélène Dehondt, Arianna Marino, Laura Butruille, Denis A Mogilenko, Arielle C Nzoussi Loubota, Oscar Chávez-Talavera, Emilie Dorchies, Emmanuelle Vallez, Joel Haas, Bruno Derudas, Antonino Bongiovanni, Meryem Tardivel, Folkert Kuipers, Philippe Lefebvre, Sophie Lestavel, Anne Tailleux, David Dombrowicz, Sandrine Caron, Bart Staels.

   OBJECTIVE: Obesity is associated with metabolic dysfunction of white adipose tissue (WAT). Activated adipocytes secrete pro-inflammatory cytokines resulting in the recruitment of pro-inflammatory macrophages, which contribute to WAT insulin resistance. The bile acid (BA)-activated nuclear Farnesoid X Receptor (FXR) controls systemic glucose and lipid metabolism. Here, we studied the role of FXR in adipose tissue function.
METHODS: We first investigated the immune phenotype of epididymal WAT (eWAT) from high fat diet (HFD)-fed whole-body FXR-deficient (FXR-/-) mice by flow cytometry and gene expression analysis. We then generated adipocyte-specific FXR-deficient (Ad-FXR-/-) mice and analyzed systemic and eWAT metabolism and immune phenotype upon HFD feeding. Transcriptomic analysis was done on mature eWAT adipocytes from HFD-fed Ad-FXR-/- mice.
RESULTS: eWAT from HFD-fed whole-body FXR-/- and Ad-FXR-/- mice displayed decreased pro-inflammatory macrophage infiltration and inflammation. Ad-FXR-/- mice showed lower blood glucose concentrations, improved systemic glucose tolerance and WAT insulin sensitivity and oxidative stress. Transcriptomic analysis identified Gsta4, a modulator of oxidative stress in WAT, as the most upregulated gene in Ad-FXR-/- mouse adipocytes. Finally, chromatin immunoprecipitation analysis showed that FXR binds the Gsta4 gene promoter.
CONCLUSIONS: These results indicate a role for the adipocyte FXR-GSTA4 axis in controlling HFD-induced inflammation and systemic glucose homeostasis.

Keywords:  Glucose metabolism; Inflammation; Nuclear receptor FXR; Oxidative stress; White adipose tissue

DOI:  https://doi.org/10.1016/j.molmet.2023.101686