Hepatic glycogenesis antagonizes lipogenesis by blocking S1P via UDPG

Science, Год журнала: 2024, Номер 383(6684)

Опубликована: Фев. 15, 2024

The identification of mechanisms to store glucose carbon in the form glycogen rather than fat hepatocytes has important implications for prevention nonalcoholic fatty liver disease (NAFLD) and other chronic metabolic diseases. In this work, we show that glycogenesis uses its intermediate metabolite uridine diphosphate (UDPG) antagonize lipogenesis, thus steering both mouse human toward storing as glycogen. underlying mechanism involves transport UDPG Golgi apparatus, where it binds site-1 protease (S1P) inhibits S1P-mediated cleavage sterol regulatory element-binding proteins (SREBPs), thereby inhibiting lipogenesis hepatocytes. Consistent with mechanism, administration is effective at treating NAFLD a model organoids. These findings indicate potential opportunity ameliorate disordered metabolism liver.

Язык: Английский

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FXR agonists for MASH therapy: Lessons and perspectives from obeticholic acid

Medicinal Research Reviews, Год журнала: 2023, Номер 44(2), С. 568 - 586

Опубликована: Окт. 30, 2023

Abstract Nonalcoholic fatty liver disease, also called metabolic dysfunction‐associated steatotic is the most common disease worldwide and has no approved pharmacotherapy. Due to its beneficial effects on regulation, inflammation suppression, cell death prevention, fibrogenesis inhibition, farnesoid X receptor (FXR) widely accepted as a promising therapeutic target for nonalcoholic steatosis (NASH) or steatohepatitis (MASH). Many FXR agonists have been developed NASH/MASH therapy. Obeticholic acid (OCA) pioneering frontrunner agonist first demonstrating success in clinical trials. Unfortunately, OCA did not receive regulatory approval NASH pharmacotherapy because moderate benefits outweigh safety risks, which may cast shadow over FXR‐based drug development NASH/MASH. This review summarizes milestones of discuss limitations, including hepatoprotection undesirable side dyslipidemia, pruritus, cholelithiasis, toxicity risk, depth. More importantly, we provide perspectives therapy NASH/MASH, hoping support successful bench‐to‐clinic transition.

Язык: Английский

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Gut microbiota in health and disease: advances and future prospects

MedComm, Год журнала: 2024, Номер 5(12)

Опубликована: Ноя. 20, 2024

Abstract The gut microbiota plays a critical role in maintaining human health, influencing wide range of physiological processes, including immune regulation, metabolism, and neurological function. Recent studies have shown that imbalances composition can contribute to the onset progression various diseases, such as metabolic disorders (e.g., obesity diabetes) neurodegenerative conditions Alzheimer's Parkinson's). These are often accompanied by chronic inflammation dysregulated responses, which closely linked specific forms cell death, pyroptosis ferroptosis. Pathogenic bacteria trigger these death pathways through toxin release, while probiotics been found mitigate effects modulating responses. Despite insights, precise mechanisms influences diseases remain insufficiently understood. This review consolidates recent findings on impact immune‐mediated inflammation‐associated conditions. It also identifies gaps current research explores potential advanced technologies, organ‐on‐chip models microbiome–gut–organ axis, for deepening our understanding. Emerging tools, single‐bacterium omics spatial metabolomics, discussed their promise elucidating microbiota's disease development.

Язык: Английский

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Protective Effect of Berberine on Acute Gastric Ulcer by Promotion of Tricarboxylic Acid Cycle-Mediated Arachidonic Acid Metabolism

Journal of Inflammation Research, Год журнала: 2024, Номер Volume 17, С. 15 - 28

Опубликована: Янв. 1, 2024

Background and Objective: Peptic ulcer is a high incidence gastrointestinal disease in China. Berberine (BBR) natural product isolated from the Chinese herb Coptis chinensis Franch that has protective effects digestive diseases. We aimed to evaluate ability of BBR attenuate acute gastric induced by one-time administration ethanol rat. Methods: Tissue pathological morphology, macroscopic score, healing rate, serum levels inflammatory cytokines nitric oxide (NO), interleukin-6 (IL-6), prostaglandin E2 (PGE2), anti-inflammatory interleukin-10 (IL-10) were used determine efficacy evaluated identify optimal dosage. Subsequently, transcriptome metabolome sequencing conducted Control, Model, dosage groups explore pathogenesis mechanism action drug. The malondialdehyde (MDA), myeloperoxidase (MPO), as well those superoxide dismutase (SOD) glutathione peroxidase (GSH-Px) determined enzyme-linked immunosorbent assay verify results transcriptomics metabolomics analyses. Results: significantly improved morphology ulcers, increased score decreased NO, IL-6, PGE2, IL-10, thus effectively alleviating severity. Transcriptome showed therapeutic effect was mainly mediated arachidonic acid metabolism pathway at gene level, which closely associated with inflammation reactive oxygen species (ROS). differentially accumulated metabolite E1, negative regulator ROS, up-regulated after administration. validation indicated pretreatment SOD GSH-Px enzyme activities, while reducing oxidative products MDA MPO. Conclusion: This study demonstrated exerts on promoting tricarboxylic cycle-mediated metabolism. Keywords: Berberine, ulcer, transcriptome, untargeted

Язык: Английский

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Sedanolide alleviates DSS-induced colitis by modulating the intestinal FXR-SMPD3 pathway in mice

Journal of Advanced Research, Год журнала: 2024, Номер unknown

Опубликована: Апрель 1, 2024

Inflammatory bowel disease (IBD) is a global with limited therapy. It reported that sedanolide exerts anti-oxidative and anti-inflammatory effects as natural phthalide, but its on IBD remain unclear. In this study, we investigated the impacts of dextran sodium sulfate (DSS)-induced colitis in mice. The mice were administered or vehicle followed by DSS administration, after which symptoms, inflammation levels, intestinal barrier function evaluated. Transcriptome analysis, 16S rRNA sequencing, targeted metabolomics analysis bile acids lipids performed. Sedanolide protected from DSS-induced colitis, suppressed inflammation, restored weakened epithelial barrier, modified gut microbiota decreasing salt hydrolase (BSH)-expressing bacteria. downregulation BSH activity increased ratio conjugated/unconjugated (BAs), thereby inhibiting farnesoid X receptor (FXR) pathway. roles FXR pathway verified using an FXR-specific agonist (fexaramine) germ-free mice, respectively. Furthermore, identified key effector ceramide, regulated sphingomyelin phosphodiesterase 3 (SMPD3). protective ceramide (d18:1/16:0) against demonstrated vitro human cell line Caco-2. could reshape flora influence BA composition, thus FXR-SMPD3 to stimulate synthesis ultimately alleviated Overall, our research revealed indicated may be clinical treatment for colitis. Additionally, lipid was shown mediate sedanolide, providing new insight into associations between metabolites.

Язык: Английский

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Ferroptosis: a potential bridge linking gut microbiota and chronic kidney disease

Cell Death Discovery, Год журнала: 2024, Номер 10(1)

Опубликована: Май 15, 2024

Abstract Ferroptosis is a novel form of lipid peroxidation-driven, iron-dependent programmed cell death. Various metabolic pathways, including those involved in and iron metabolism, contribute to ferroptosis regulation. The gut microbiota not only supplies nutrients energy the host, but also plays crucial role immune modulation balance. In this review, we explore pathways associated with impact on host metabolism. We subsequently summarize recent studies influence regulation by discuss potential mechanisms through which affects ferroptosis. Additionally, conduct bibliometric analysis relationship between context chronic kidney disease. This can provide new insights into current research status future microbiota.

Язык: Английский

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Understanding the role of ursodeoxycholic acid and gut microbiome in non-alcoholic fatty liver disease: current evidence and perspectives

Frontiers in Pharmacology, Год журнала: 2024, Номер 15

Опубликована: Март 21, 2024

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic disease, resulting in a huge medical burden worldwide. Accumulating evidence suggests that gut microbiome and bile acids play pivotal roles during development of NAFLD. Patients with NAFLD exhibit unique signatures intestinal marked by priority Gram-negative bacteria, decreased ratio

Язык: Английский

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Unveiling the role of ferroptosis in the progression from NAFLD to NASH: recent advances in mechanistic understanding

Frontiers in Endocrinology, Год журнала: 2024, Номер 15

Опубликована: Июль 4, 2024

Non-alcoholic fatty liver disease (NAFLD) is a prevalent and significant global public health issue. Nonalcoholic steatohepatitis (NASH) represents an advanced stage of NAFLD in terms pathology. However, the intricate mechanisms underlying progression from to NASH remain elusive. Ferroptosis, characterized by iron-dependent cell death distinguished other forms based on morphological, biochemical, genetic criteria, has emerged as potential participant with pivotal role driving progression. Nevertheless, its precise mechanism remains poorly elucidated. In this review article, we comprehensively summarize pathogenesis NAFLD/NASH ferroptosis while highlighting recent advances understanding mechanistic involvement NAFLD/NASH.

Язык: Английский

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Bile acid receptor FXR promotes intestinal epithelial ferroptosis and subsequent ILC3 dysfunction in neonatal necrotizing enterocolitis

Immunity, Год журнала: 2025, Номер unknown

Опубликована: Фев. 1, 2025

Язык: Английский

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Circadian Control of Hepatic Ischemia/Reperfusion Injury via HSD17B13-Mediated Autophagy in Hepatocytes

Journal of Hepatology, Год журнала: 2025, Номер unknown

Опубликована: Март 1, 2025

Язык: Английский

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