bims-faldev 2024-07-07 papers

Issue of 2024‒07‒07
six papers selected by
Stepheny Carneiro de Campos Zani, Universidade Estadual de Campinas

Nat Commun. 2024 Jun 29. 15(1): 5506

IFNγ-IL12 axis regulates intercellular crosstalk in metabolic dysfunction-associated steatotic liver disease.

Obesity is a major cause of metabolic dysfunction-associated steatohepatitis (MASH) and is characterized by inflammation and insulin resistance. Interferon-γ (IFNγ) is a pro-inflammatory cytokine elevated in obesity and modulating macrophage functions. Here, we show that male mice with loss of IFNγ signaling in myeloid cells (Lyz-IFNγR2-/-) are protected from diet-induced insulin resistance despite fatty liver. Obesity-mediated liver inflammation is also attenuated with reduced interleukin (IL)-12, a cytokine primarily released by macrophages, and IL-12 treatment in vivo causes insulin resistance by impairing hepatic insulin signaling. Following MASH diets, Lyz-IFNγR2-/- mice are rescued from developing liver fibrosis, which is associated with reduced fibroblast growth factor (FGF) 21 levels. These results indicate critical roles for IFNγ signaling in macrophages and their release of IL-12 in modulating obesity-mediated insulin resistance and fatty liver progression to MASH. In this work, we identify the IFNγ-IL12 axis in regulating intercellular crosstalk in the liver and as potential therapeutic targets to treat MASH.

DOI: https://doi.org/10.1038/s41467-024-49633-y

FASEB J. 2024 Jul 15. 38(13): e23766

Dynamic changes of gut microbiota in mouse models of metabolic dysfunction-associated steatohepatitis and its transition to hepatocellular carcinoma.

Yu-Li Wang, Chang Liu, Yong-Yu Yang, Li Zhang, Xiao Guo, Chen Niu, Ning-Ping Zhang, Jia Ding, Jian Wu.

Dysbiosis of gut microbiota may account for pathobiology in simple fatty liver (SFL), metabolic dysfunction-associated steatohepatitis (MASH), fibrotic progression, and transformation to MASH-associated hepatocellular carcinoma (MASH-HCC). The aim of the present study is to investigate gut dysbiosis in this progression. Fecal microbial rRNA-16S sequencing, absolute quantification, histopathologic, and biochemical tests were performed in mice fed high fat/calorie diet plus high fructose and glucose in drinking water (HFCD-HF/G) or control diet (CD) for 2, 16 weeks, or 14 months. Histopathologic examination verified an early stage of SFL, MASH, fibrotic, or MASH-HCC progression with disturbance of lipid metabolism, liver injury, and impaired gut mucosal barrier as indicated by loss of occludin in ileum mucosa. Gut dysbiosis occurred as early as 2 weeks with reduced α diversity, expansion of Kineothrix, Lactococcus, Akkermansia; and shrinkage in Bifidobacterium, Lactobacillus, etc., at a genus level. Dysbiosis was found as early as MAHS initiation, and was much more profound through the MASH-fibrotic and oncogenic progression. Moreover, the expansion of specific species, such as Lactobacillus johnsonii and Kineothrix alysoides, was confirmed by an optimized method for absolute quantification. Dynamic alterations of gut microbiota were characterized in three stages of early SFL, MASH, and its HCC transformation. The findings suggest that the extent of dysbiosis was accompanied with MASH progression and its transformation to HCC, and the shrinking or emerging of specific microbial species may account at least in part for pathologic, metabolic, and immunologic alterations in fibrogenic progression and malignant transition in the liver.

Keywords: absolute quantification; dysbiosis; gut microbiota; gut–liver axis; metabolic dysfunction‐associated steatotic liver disease

DOI: https://doi.org/10.1096/fj.202400573RR

World J Gastroenterol. 2024 Jun 21. 30(23): 2964-2980

Role of gut-liver axis and glucagon-like peptide-1 receptor agonists in the treatment of metabolic dysfunction-associated fatty liver disease.

Jakub Rochoń, Piotr Kalinowski, Ksenia Szymanek-Majchrzak, Michał Grąt.

Metabolic dysfunction-associated fatty liver disease (MAFLD) is a hepatic manifestation of the metabolic syndrome. It is one of the most common liver diseases worldwide and shows increasing prevalence rates in most countries. MAFLD is a progressive disease with the most severe cases presenting as advanced fibrosis or cirrhosis with an increased risk of hepatocellular carcinoma. Gut microbiota play a significant role in the pathogenesis and progression of MAFLD by disrupting the gut-liver axis. The mechanisms involved in maintaining gut-liver axis homeostasis are complex. One critical aspect involves preserving an appropriate intestinal barrier permeability and levels of intestinal lumen metabolites to ensure gut-liver axis functionality. An increase in intestinal barrier permeability induces metabolic endotoxemia that leads to steatohepatitis. Moreover, alterations in the absorption of various metabolites can affect liver metabolism and induce liver steatosis and fibrosis. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are a class of drugs developed for the treatment of type 2 diabetes mellitus. They are also commonly used to combat obesity and have been proven to be effective in reversing hepatic steatosis. The mechanisms reported to be involved in this effect include an improved regulation of glycemia, reduced lipid synthesis, β-oxidation of free fatty acids, and induction of autophagy in hepatic cells. Recently, multiple peptide receptor agonists have been introduced and are expected to increase the effectiveness of the treatment. A modulation of gut microbiota has also been observed with the use of these drugs that may contribute to the amelioration of MAFLD. This review presents the current understanding of the role of the gut-liver axis in the development of MAFLD and use of members of the GLP-1 RA family as pleiotropic agents in the treatment of MAFLD.

Keywords: Bariatric surgery; Gastrointestinal microbiota; Glucagon-like peptide-1; Glucagon-like peptide-2; Metabolic dysfunction-associated fatty liver disease; Metabolic dysfunction-associated steatohepatitis; Metabolic syndrome; Non-alcoholic fatty liver disease; Non-alcoholic steatohepatitis; Obesity

DOI: https://doi.org/10.3748/wjg.v30.i23.2964

Expert Opin Pharmacother. 2024 Jul 02. 1-15

Pharmacotherapeutic options for metabolic dysfunction-associated steatotic liver disease: where are we today?

Tobias Puengel, Frank Tacke.

INTRODUCTION: Metabolic dysfunction-associated steatotic liver disease (MASLD) is defined by hepatic steatosis and cardiometabolic risk factors like obesity, type 2 diabetes, and dyslipidemia. Persistent metabolic injury may promote inflammatory processes resulting in metabolic dysfunction-associated steatohepatitis (MASH) and liver fibrosis. Mechanistic insights helped to identify potential drug targets, thereby supporting the development of novel compounds modulating disease drivers.AREAS COVERED: The U.S. Food and Drug Administration has recently approved the thyroid hormone receptor β-selective thyromimetic resmetirom as the first compound to treat MASH and liver fibrosis. This review provides a comprehensive overview of current and potential future pharmacotherapeutic options and their modes of action. Lessons learned from terminated clinical trials are discussed together with the first results of trials investigating novel combinational therapeutic approaches.
EXPERT OPINION: Approval of resmetirom as the first anti-MASH agent may revolutionize the therapeutic landscape. However, long-term efficacy and safety data for resmetirom are currently lacking. In addition, heterogeneity of MASLD reflects a major challenge to define effective agents. Several lead compounds demonstrated efficacy in reducing obesity and hepatic steatosis, while anti-inflammatory and antifibrotic effects of monotherapy appear less robust. Better mechanistic understanding, exploration of combination therapies, and patient stratification hold great promise for MASLD therapy.

Keywords: NAFLD; NASH; glucagon-like peptide-1 (GLP-1); incretins; liver fibrosis; nonalcoholic fatty liver disease; peroxisome proliferator activated receptors (PPARs); thyroid hormone receptor β (THRβ)

DOI: https://doi.org/10.1080/14656566.2024.2374463

Diabetes Metab Syndr Obes. 2024 ;17 2597-2605

The Association Between Neutrophil/High-Density Lipoprotein Cholesterol Ratio and Non-Alcoholic Fatty Liver Disease in a Healthy Population.

Zhuoya Jia, Zelin Li, Shuchun Chen.

Objective: Non-alcoholic fatty liver disease (NAFLD) is characterized by abnormal lipid metabolism and inflammation. This study aimed to investigate the relationship between neutrophil-HDL cholesterol ratio (NHR) and NAFLD in a healthy population.Methods: 1881 healthy people who underwent a physical examination from August to December 2023 at the Hebei General Hospital were chosen for this cross-sectional study. 936 individuals were ultimately included thanks to propensity matching and exclusion criteria. Ultrasound was used to diagnose fatty liver and a t-test or Mann-Whitney test was used to compare the clinical characteristics of participants between groups with and without fatty liver. Logistic regression was used to construct a new model that included NHR. The predictive value of NHR as well as the new model for NAFLD in a healthy population was assessed using logistic regression and subject work characteristic curves.
Results: NHR levels were higher among participants in the NAFLD group than those without NAFLD(P<0.05). NHR is a risk factor for NAFLD in a healthy population(P<0.05). The odds ratios (ORs) of NHR for predicting NAFLD in Model I (adjusted for sex, age, and BMI) and Model II (adjusted for sex, age, BMI, HbA1c, TC, TG, and ALT) were 1.166 (1.022, 1.331) and 1.248 (1.110, 1.402)(P<0.05). The new model created by logistic regression predicted NAFLD with an area under the curve of 0.676 (0.645, 0.706). Compared to participants in the low NHR group, the high NHR group exhibited a higher prevalence of NAFLD(p<0.05).
Conclusion: NHR is associated with NAFLD, which is a good predictor of NAFLD in a healthy population.

Keywords: neutrophil/high-density lipoprotein cholesterol ratio; nonalcoholic fatty liver disease

DOI: https://doi.org/10.2147/DMSO.S464406

J Transl Med. 2024 Jul 04. 22(1): 623

Increased secretion of adipocyte-derived extracellular vesicles is associated with adipose tissue inflammation and the mobilization of excess lipid in human obesity.

BACKGROUND: Obesity is a worldwide epidemic characterized by adipose tissue (AT) inflammation. AT is also a source of extracellular vesicles (EVs) that have recently been implicated in disorders related to metabolic syndrome. However, our understanding of mechanistic aspect of obesity's impact on EV secretion from human AT remains limited.METHODS: We investigated EVs from human Simpson Golabi Behmel Syndrome (SGBS) adipocytes, and from AT as well as plasma of subjects undergoing bariatric surgery. SGBS cells were treated with TNFα, palmitic acid, and eicosapentaenoic acid. Various analyses, including nanoparticle tracking analysis, electron microscopy, high-resolution confocal microscopy, and gas chromatography-mass spectrometry, were utilized to study EVs. Plasma EVs were analyzed with imaging flow cytometry.
RESULTS: EVs from mature SGBS cells differed significantly in size and quantity compared to preadipocytes, disagreeing with previous findings in mouse adipocytes and indicating that adipogenesis promotes EV secretion in human adipocytes. Inflammatory stimuli also induced EV secretion, and altered EV fatty acid (FA) profiles more than those of cells, suggesting the role of EVs as rapid responders to metabolic shifts. Visceral AT (VAT) exhibited higher EV secretion compared to subcutaneous AT (SAT), with VAT EV counts positively correlating with plasma triacylglycerol (TAG) levels. Notably, the plasma EVs of subjects with obesity contained a higher number of adiponectin-positive EVs than those of lean subjects, further demonstrating higher AT EV secretion in obesity. Moreover, plasma EV counts of people with obesity positively correlated with body mass index and TNF expression in SAT, connecting increased EV secretion with AT expansion and inflammation. Finally, EVs from SGBS adipocytes and AT contained TAGs, and EV secretion increased despite signs of less active lipolytic pathways, indicating that AT EVs could be involved in the mobilization of excess lipids into circulation.
CONCLUSIONS: We are the first to provide detailed FA profiles of human AT EVs. We report that AT EV secretion increases in human obesity, implicating their role in TAG transport and association with adverse metabolic parameters, thereby emphasizing their role in metabolic disorders. These findings promote our understanding of the roles that EVs play in human AT biology and metabolic disorders.

Keywords: Adipocyte; Adipose tissue; Extracellular vesicles; Fatty acids; Inflammation; Obesity

DOI: https://doi.org/10.1186/s12967-024-05249-w