bims-liverm 2022-12-11 papers

Issue of 2022–12–11
eight papers selected by

Dtsch Arztebl Int. 2022 Sep 05. pii: arztebl.m2022.0177. [Epub ahead of print]119(35-36): 609

Role of the Gut Microbiome and Bile Acids.

DOI: https://doi.org/10.3238/arztebl.m2022.0177

Diabetes Res Clin Pract. 2022 Nov 26. pii: S0168-8227(22)01005-1. [Epub ahead of print]194 110191

The association between changes in hepatic steatosis and hepatic fibrosis with cardiovascular outcomes and mortality in patients with New-Onset type 2 Diabetes: A nationwide cohort study.

Jiyun Park, Gyuri Kim, Bong-Sung Kim, Kyung-Do Han, So Yoon Kwon, So Hee Park, You-Bin Lee, Sang-Man Jin, Jae Hyeon Kim.

AIM: Non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM) have a synergistic effect on cardiovascular disease (CVD). We investigated the association of changes in hepatic steatosis and advanced hepatic fibrosis with risk of CVD and mortality in new-onset T2DM.
METHODS: Using the Korean National Health Insurance dataset, we included 120,256 patients with new-onset T2DM. Hepatic steatosis and advanced hepatic fibrosis were determined using the fatty liver index (FLI) and BARD score. According to the changes of the two scores over two years, patients were divided into four groups and analyzed for development of myocardial infarction (MI), stroke, heart failure (HF), and mortality.
RESULTS: Incident hepatic steatosis was associated with increased development of stroke, HF, and mortality compared with non-NAFLD (all p < 0.05). Regression and persistent hepatic steatosis were associated with increased risk of MI, stroke, HF, and mortality compared with non-NAFLD (all p < 0.05). Persistent advanced hepatic fibrosis was associated with increased risk of stroke, HF, and mortality (all p < 0.05).) Compared with persistent hepatic fibrosis, regression of hepatic fibrosis was associated with decreased risk of stroke, HF, and mortality (all p < 0.05).
CONCLUSIONS: Changes in FLI or BARD score were associated with CVD and mortality in new-onset T2DM.

Keywords: BARD score; Fatty liver index; Heart failure; Mortality; Myocardial infarction; Stroke

DOI: https://doi.org/10.1016/j.diabres.2022.110191

Scand J Clin Lab Invest. 2022 Dec 09. 1-10

Efficacy of bile acid profiles in diagnosing and staging of alcoholic liver disease.

Gaixia Zhang, Haizhen Chen, Wenbo Ren, Jing Huang.

AIM: The diagnosis of alcoholic liver disease (ALD) is still a great challenge. Therefore, the purpose of this study is to identify and characterize new metabolomic biomarkers for the diagnosis and staging of ALD.
METHODS: A total of 127 patients with early liver injury, 40 patients with alcoholic cirrhosis (ALC) and 40 healthy controls were included in this study. Patients with early liver injury included 45 patients with alcoholic liver disease (ALD), 40 patients with non-alcoholic fatty liver disease (NAFLD) and 40 patients with viral liver disease (VLD). The differential metabolites in serum samples were analyzed using ultra-high-performance liquid chromatography-quadrupole/time-of-flight mass spectrometry, and partial metabolites in the differential metabolic pathway were identified by liquid chromatography- tandem mass spectrometry.
RESULTS: A total of 40 differential metabolites and five differential metabolic pathways in the four groups of patients with early liver disease and healthy controls were found, and the metabolic pathway of primary bile acid (BA) biosynthesis was the pathway that included the most differential metabolites. Therefore, 22 BA profiles were detected. The results revealed that the changes of BA profiles were most pronounced in patients with ALD compared with patients with NAFLD and VLD, in whom 12 differential BAs were diagnostic markers of ALD (AUC = 0.883). The 19 differential BAs in ALC and ALD were diagnostic markers of the stage of alcoholic hepatic fibrosis (AUC = 0.868).
CONCLUSION: BA profiles are potential indicators in the diagnosis of ALD and evaluation of different stages.

Keywords: Alcoholic liver disease; alcoholic cirrhosis; bile acids; metabolomics; transient elastography

DOI: https://doi.org/10.1080/00365513.2022.2151508

Toxicol In Vitro. 2022 Dec 03. pii: S0887-2333(22)00231-4. [Epub ahead of print] 105533

Novel insights into bile acid detoxification via CYP, UGT and SULT enzymes.

Vlasia Kastrinou Lampou, Birk Poller, Felix Huth, Audrey Fischer, Gerd A Kullak-Ublick, Michael Arand, Heiko S Schadt, Gian Camenisch.

Bile acid (BA) homeostasis is a complex and precisely regulated process to prevent impaired BA flow and the development of cholestasis. Several reactions, namely hydroxylation, glucuronidation and sulfation are involved in BA detoxification. In the present study, we employed a comprehensive approach to identify the key enzymes involved in BA metabolism using human recombinant enzymes, human liver microsomes (HLM) and human liver cytosol (HLC). We showed that CYP3A4 was a crucial step for the metabolism of several BAs and their taurine and glycine conjugated forms and quantitatively described their metabolites. Glucuronidation and sulfation were also identified as important drivers of the BA detoxification process in humans. Moreover, lithocholic acid (LCA), the most hydrophobic BA with the highest toxicity potential, was a substrate for all investigated processes, demonstrating the importance of hepatic metabolism for its clearance. Collectively, this study identified CYP3A4, UGT1A3, UGT2B7 and SULT2A1 as the major contributing (metabolic) processes in the BA detoxification network. Inhibition of these enzymes by drug candidates is therefore considered as a critical mechanism in the manifestation of drug-induced cholestasis in humans and should be addressed during the pre-clinical development.

Keywords: Bile acid metabolism; CYP3A4; Glucuronidation; LCA; Lithocholic acid; Sulfation

DOI: https://doi.org/10.1016/j.tiv.2022.105533

iScience. 2022 Dec 22. 25(12): 105569

Hepatocyte-derived GDF15 suppresses feeding and improves insulin sensitivity in obese mice.

Bingxian Xie, Anjana Murali, Amber M Vandevender, Jeffrey Chen, Agustin Gil Silva, Fiona M Bello, Byron Chuan, Harinath Bahudhanapati, Ian Sipula, Nikolaos Dedousis, Faraaz A Shah, Christopher P O'Donnell, Jonathan K Alder, Michael J Jurczak.

Growth differentiation factor 15 (GDF15) is a stress-induced secreted protein whose circulating levels are increased in the context of obesity. Recombinant GDF15 reduces body weight and improves glycemia in obese models, which is largely attributed to the central action of GDF15 to suppress feeding and reduce body weight. Despite these advances in knowledge, the tissue-specific sites of GDF15 production during obesity are unknown, and the effects of modulating circulating GDF15 levels on insulin sensitivity have not been evaluated directly. Here, we demonstrate that hepatocyte Gdf15 expression is sufficient for changes in circulating levels of GDF15 during obesity and that restoring Gdf15 expression specifically in hepatocytes of Gdf15 knockout mice results in marked improvements in hyperinsulinemia, hepatic insulin sensitivity, and to a lesser extent peripheral insulin sensitivity. These data support that liver hepatocytes are the primary source of circulating GDF15 in obesity.

Keywords: Cellular physiology; Diabetology; Molecular genetics

DOI: https://doi.org/10.1016/j.isci.2022.105569

Metabolism. 2022 Dec 01. pii: S0026-0495(22)00249-9. [Epub ahead of print] 155371

Impaired hepatic glucose metabolism and liver-α-cell axis in mice with liver-specific ablation of the hepatocyte nuclear factor 4α (Hnf4a) gene.

Efstathia Thymiakou, Maria Tzardi, Dimitris Kardassis.

BACKGROUND: Hnf4a gene ablation in mouse liver causes hepatic steatosis, perturbs HDL structure and function and affects many pathways and genes related to glucose metabolism. Our aim here was to investigate the role of liver HNF4A in glucose homeostasis.
METHODS: Serum and tissue samples were obtained from Alb-Cre;Hnf4afl/fl (H4LivKO) mice and their littermate Hnf4afl/fl controls. Fasting glucose and insulin, glucose tolerance, insulin tolerance and glucagon challenge tests were performed by standard procedures. Binding of HNF4A to DNA was assessed by chromatin immunoprecipitation assays. Gene expression analysis was performed by quantitative reverse transcription PCR.
RESULTS: H4LivKO mice presented lower blood levels of fasting glucose, improved glucose tolerance, increased serum lactate levels and reduced response to glucagon challenge compared to their control littermates. Insulin signaling in the liver was reduced despite the increase in serum insulin levels. H4LivKO mice showed altered expression of genes involved in glycolysis, gluconeogenesis and glycogen metabolism in the liver. The expression of the gene encoding the glucagon receptor (Gcgr) was markedly reduced in H4LivKO liver and chromatin immunoprecipitation assays revealed specific and strong binding of HNF4A to the Gcgr promoter. H4LivKO mice presented increased amino acid concentration in the serum, α-cell hyperplasia and a dramatic increase in glucagon levels suggesting an impairment of the liver-α-cell axis. Glucose administration in the drinking water of H4LivKO mice resulted in an impressive extension of survival. The expression of several genes related to non-alcoholic fatty liver disease progression to more severe liver pathologies, including Mcp1, Gdf15, Igfbp-1 and Hmox1, was increased in H4LivKO mice as early as 6-weeks of age and this increased expression was sustained until the endpoint of the study.
CONCLUSIONS: Our results reveal a novel role of liver HNF4A in controlling blood glucose levels via regulation of glucagon signaling. In combination with the steatotic phenotype, our results suggest that H4LivKO mice could serve as a valuable model for studying glucose homeostasis in the context of non-alcoholic fatty liver disease.

Keywords: Glucagon; Glucagon receptor; Glucose; Hepatocyte nuclear factor 4; Liver; Non-alcoholic fatty liver disease

DOI: https://doi.org/10.1016/j.metabol.2022.155371

Cell Mol Life Sci. 2022 Dec 07. 80(1): 4

Liver-derived metabolites as signaling molecules in fatty liver disease.

Umur Keles, Jin Rong Ow, Katharina Barbara Kuentzel, Li Na Zhao, Philipp Kaldis.

Excessive fat accumulation in the liver has become a major health threat worldwide. Unresolved fat deposition in the liver can go undetected until it develops into fatty liver disease, followed by steatohepatitis, fibrosis, cirrhosis, and eventually hepatocellular carcinoma. Lipid deposition in the liver is governed by complex communication, primarily between metabolic organs. This can be mediated by hormones, organokines, and also, as has been more recently discovered, metabolites. Although how metabolites from peripheral organs affect the liver is well documented, the effect of metabolic players released from the liver during the development of fatty liver disease or associated comorbidities needs further attention. Here we focus on interorgan crosstalk based on metabolites released from the liver and how these molecules act as signaling molecules in peripheral tissues. Due to the liver's specific role, we are covering lipid and bile mechanism-derived metabolites. We also discuss the high sucrose intake associated with uric acid release from the liver. Excessive fat deposition in the liver during fatty liver disease development reflects disrupted metabolic processes. As a response, the liver secretes a variety of signaling molecules as well as metabolites which act as a footprint of the metabolic disruption. In the coming years, the reciprocal exchange of metabolites between the liver and other metabolic organs will gain further importance and will help to better understand the development of fatty liver disease and associated diseases.

Keywords: Bile acids; Fatty liver disease; Free fatty acids; Hepatokines; Interorgan crosstalk; Liver; Metabolites; Metabolomics; NAFLD; NASH; Organokines; Uric acid

DOI: https://doi.org/10.1007/s00018-022-04658-8