Bile acid metabolism and signaling, the microbiota, and metabolic disease

Pharmacology & Therapeutics, Год журнала: 2022, Номер 237, С. 108238 - 108238

Опубликована: Июль 2, 2022

Язык: Английский

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Crosstalk between Oxidative Stress and Inflammatory Liver Injury in the Pathogenesis of Alcoholic Liver Disease

International Journal of Molecular Sciences, Год журнала: 2022, Номер 23(2), С. 774 - 774

Опубликована: Янв. 11, 2022

Alcoholic liver disease (ALD) is characterized by the injury, inflammation, and scarring in owing to excessive alcohol consumption. Currently, ALD a leading cause for transplantation. Therefore, extensive studies (in vitro, experimental models humans) are needed elucidate pathological features pathogenic mechanisms underlying ALD. Notably, oxidative changes have been recognized as signature trait of Progression linked generation highly reactive free radicals reactions involving ethanol its metabolites. Furthermore, hepatic stress promotes tissue injury and, turn, stimulates inflammatory responses liver, forming loop that progression Accordingly, accumulating further knowledge on relationship between inflammation may help establish viable therapeutic approach treating

Язык: Английский

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Engineered human hepatocyte organoids enable CRISPR-based target discovery and drug screening for steatosis

Nature Biotechnology, Год журнала: 2023, Номер 41(11), С. 1567 - 1581

Опубликована: Фев. 23, 2023

Abstract The lack of registered drugs for nonalcoholic fatty liver disease (NAFLD) is partly due to the paucity human-relevant models target discovery and compound screening. Here we use human fetal hepatocyte organoids model first stage NAFLD, steatosis, representing three different triggers: free acid loading, interindividual genetic variability (PNPLA3 I148M) monogenic lipid disorders ( APOB MTTP mutations). Screening drug candidates revealed compounds effective at resolving steatosis. Mechanistic evaluation uncovered repression de novo lipogenesis as convergent molecular pathway. We present FatTracer, a CRISPR screening platform identify steatosis modulators putative targets using −/− organoids. From screen targeting 35 genes implicated in metabolism and/or NAFLD risk, FADS2 (fatty desaturase 2) emerged an important determinant hepatic Enhancement expression increases polyunsaturated abundancy which, turn, reduces lipogenesis. These organoid facilitate study etiology targets.

Язык: Английский

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Bile acid and receptors: biology and drug discovery for nonalcoholic fatty liver disease

Acta Pharmacologica Sinica, Год журнала: 2022, Номер 43(5), С. 1103 - 1119

Опубликована: Фев. 25, 2022

Язык: Английский

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Bile acid signaling in the regulation of whole body metabolic and immunological homeostasis

Science China Life Sciences, Год журнала: 2023, Номер 67(5), С. 865 - 878

Опубликована: Июль 27, 2023

Язык: Английский

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Targeting the gut microbiota and its metabolites for type 2 diabetes mellitus

Frontiers in Endocrinology, Год журнала: 2023, Номер 14

Опубликована: Май 9, 2023

Type 2 diabetes mellitus (T2DM) is a metabolic disorder characterized by hyperglycemia and insulin resistance. The incidence of T2DM increasing globally, growing body evidence suggests that gut microbiota dysbiosis may contribute to the development this disease. Gut microbiota-derived metabolites, including bile acids, lipopolysaccharide, trimethylamine-N-oxide, tryptophan indole derivatives, short-chain fatty have been shown be involved in pathogenesis T2DM, playing key role host-microbe crosstalk. This review aims summarize molecular links between metabolites T2DM. Additionally, we potential therapy treatments for using probiotics, prebiotics, fecal transplantation other methods modulate its metabolites. Clinical trials investigating critically discussed. highlights targeting could therapeutic strategy prevention treatment

Язык: Английский

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NAFLD and NASH: etiology, targets and emerging therapies

Drug Discovery Today, Год журнала: 2024, Номер 29(3), С. 103910 - 103910

Опубликована: Фев. 1, 2024

Язык: Английский

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Gut microbiota alters host bile acid metabolism to contribute to intrahepatic cholestasis of pregnancy

Nature Communications, Год журнала: 2023, Номер 14(1)

Опубликована: Март 9, 2023

Abstract Intrahepatic cholestasis of pregnancy (ICP) is a female pregnancy-specific disorder that characterized by increased serum bile acid and adverse fetal outcomes. The aetiology mechanism ICP are poorly understood; thus, existing therapies have been largely empiric. Here we show the gut microbiome differed significantly between individuals with healthy pregnant women, colonization from patients was sufficient to induce in mice. microbiomes were primarily Bacteroides fragilis ( B. ), able promote inhibiting FXR signaling via its BSH activity modulate metabolism. -mediated inhibition responsible for excessive synthesis interrupted hepatic excretion ultimately initiation ICP. We propose modulation microbiota-bile acid-FXR axis may be value treatment.

Язык: Английский

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Breaking the barriers: the role of gut homeostasis in Metabolic-Associated Steatotic Liver Disease (MASLD)

Gut Microbes, Год журнала: 2024, Номер 16(1)

Опубликована: Март 21, 2024

Obesity, insulin resistance (IR), and the gut microbiome intricately interplay in Metabolic-associated Steatotic Liver Disease (MASLD), previously known as Non-Alcoholic Fatty (NAFLD), a growing health concern. The complex progression of MASLD extends beyond liver, driven by "gut-liver axis," where diet, genetics, gut-liver interactions influence disease development. pathophysiology involves excessive liver fat accumulation, hepatocyte dysfunction, inflammation, fibrosis, with subsequent risk hepatocellular carcinoma (HCC). gut, tripartite barrier, mechanical, immune, microbial components, engages constant communication liver. Recent evidence links dysbiosis disrupted barriers to systemic inflammation progression. Toll-like receptors (TLRs) mediate immunological crosstalk between recognizing structures triggering immune responses. "multiple hit model" development factors like resistance, dysbiosis, genetics/environmental elements disrupting axis, leading impaired intestinal barrier function increased permeability. Clinical management strategies encompass dietary interventions, physical exercise, pharmacotherapy targeting bile acid (BA) metabolism, modulation approaches through prebiotics, probiotics, symbiotics, fecal microbiota transplantation (FMT). This review underscores microbiome, their impact on therapeutic prospects.

Язык: Английский

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Gut microbiota-bile acid crosstalk regulates murine lipid metabolism via the intestinal FXR-FGF19 axis in diet-induced humanized dyslipidemia

Microbiome, Год журнала: 2023, Номер 11(1)

Опубликована: Ноя. 25, 2023

Diet-induced dyslipidemia is linked to the gut microbiota, but causality of microbiota-host interaction affecting lipid metabolism remains controversial. Here, humanized mice model was successfully built by using fecal microbiota transplantation from dyslipidemic donors (FMT-dd) study causal role in diet-induced dyslipidemia.We demonstrated that FMT-dd reshaped increasing Faecalibaculum and Ruminococcaceae UCG-010, which then elevated serum cholicacid (CA), chenodeoxycholic acid (CDCA), deoxycholic (DCA), reduced bile synthesis increased cholesterol accumulation via hepatic farnesoid X receptor-small heterodimer partner (FXR-SHP) axis. Nevertheless, high-fat diet led decreased Muribaculum induced FMT-dd, resulted intestinal hyodeoxycholic (HDCA), raised absorption receptor-fibroblast growth factor 19 (FXR-FGF19) axis.Our studies implicated FXR responsible for regulation mediated microbiota-bile crosstalk. Video Abstract.

Язык: Английский

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