In obesity-associated non-alcoholic steatohepatitis (NASH), persistent hepatocellular damage and inflammation are key drivers of fibrosis, which is the main determinant of NASH-associated mortality. The short-chain fatty acid butyrate can exert metabolic improvements and anti-inflammatory activities in NASH. However, its effects on NASH-associated liver fibrosis remain unclear. Putative antifibrotic effects of butyrate were studied in Ldlr-/-.Leiden mice fed an obesogenic diet (HFD) containing 2.5% (/) butyrate for 38 weeks and compared with a HFD-control group. Antifibrotic mechanisms of butyrate were further investigated in TGF-β-stimulated primary human hepatic stellate cells (HSC). HFD-fed mice developed obesity, insulin resistance, increased plasma leptin levels, adipose tissue inflammation, gut permeability, dysbiosis, and NASH-associated fibrosis. Butyrate corrected hyperinsulinemia, lowered plasma leptin levels, and attenuated adipose tissue inflammation, without affecting gut permeability or microbiota composition. Butyrate lowered plasma ALT and CK-18M30 levels and attenuated hepatic steatosis and inflammation. Butyrate inhibited fibrosis development as demonstrated by decreased hepatic collagen content and Sirius-red-positive area. In TGF-β-stimulated HSC, butyrate dose-dependently reduced collagen deposition and decreased procollagen1α1 and PAI1 protein expression. Transcriptomic analysis and subsequent pathway and upstream regulator analysis revealed deactivation of specific non-canonical TGF-β signaling pathways Rho-like GTPases and PI3K/AKT and other important pro-fibrotic regulators (e.g., YAP/TAZ, MYC) by butyrate, providing a potential rationale for its antifibrotic effects. In conclusion, butyrate protects against obesity development, insulin resistance-associated NASH, and liver fibrosis. These antifibrotic effects are at least partly attributable to a direct effect of butyrate on collagen production in hepatic stellate cells, involving inhibition of non-canonical TGF-β signaling pathways.
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http://dx.doi.org/10.3390/biomedicines9121954 | DOI Listing |
Elife
January 2025
Department of Anatomy and Neurobiology, Boston University Chobanian & Avedisian School of Medicine, Boston, United States.
The basal ganglia (BG) are an evolutionarily conserved and phylogenetically old set of sub-cortical nuclei that guide action selection, evaluation, and reinforcement. The entopeduncular nucleus (EP) is a major BG output nucleus that contains a population of GABA/glutamate cotransmitting neurons (EP) that specifically target the lateral habenula (LHb) and whose function in behavior remains mysterious. Here, we use a probabilistic switching task that requires an animal to maintain flexible relationships between action selection and evaluation to examine when and how GABA/glutamate cotransmitting neurons contribute to behavior.
View Article and Find Full Text PDFCurr Res Food Sci
December 2024
UMR 454 MEDIS, Microbiologie Environnement Digestif et Santé, Université Clermont Auvergne - INRAE, Clermont-Ferrand, France.
Associated to various illnesses, Western Diet (WD) is acknowledged to have deleterious effects on human gut microbiota, decreasing bacterial diversity, lowering gut bacteria associated to health (such as , while increasing those linked to diseases (e.g., ).
View Article and Find Full Text PDFCurr Res Toxicol
December 2024
Institute of Toxicology, College of Preventive Medicine, Army Medical University, Chongqing 400038, China.
Rotenone is a natural compound from plants. It is widely used in pesticides because of highly toxic to insects and fish. However, lots of research has reported that rotenone has neurotoxic effects in humans.
View Article and Find Full Text PDFFront Microbiol
January 2025
Department of Clinical Pharmacy, Key Laboratory of Basic Pharmacology of Guizhou Province and School of Pharmacy, Zunyi Medical University, Zunyi, China.
Background: The role of gut microbiota in inflammatory disease development and progression has been recognized more recently. Inflammasome-mediated pyroptosis in involved in these diseases. This complex relationship between gut microbiota and inflammasome-mediated pyroptosis provides an important field of research.
View Article and Find Full Text PDFFront Microbiol
January 2025
School of Acupuncture-Moxibustion and Tuina, Chengdu University of Traditional Chinese Medicine, Chengdu, China.
Objective: This study aimed to investigate the impact of electroacupuncture (EA) on blood glucose levels, gut microbiota, short-chain fatty acids (SCFAs), and glucagon-like peptide-1 (GLP-1) in a rat model of type 2 diabetes mellitus (T2DM).
Methods: Forty Sprague-Dawley (SD) rats were randomly assigned to five groups (n = 8/group) using a random number table: normal control, T2DM model, electroacupuncture (EA), EA + antibiotics (EA + A), and antibiotics (A). The normal rats received a standard diet and saline gavage, while the other groups were fed a high-fat diet and emulsion.
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