NAFLD: Mechanisms, Treatments, and Biomarkers

Biomolecules, Journal Year: 2022, Volume and Issue: 12(6), P. 824 - 824

Published: June 13, 2022

Nonalcoholic fatty liver disease (NAFLD), recently renamed metabolic-associated (MAFLD), is one of the most common causes diseases worldwide. NAFLD growing in parallel with obesity epidemic. No pharmacological treatment available to treat NAFLD, specifically. The reason might be that a multi-factorial an incomplete understanding mechanisms involved, absence accurate and inexpensive imaging tools, lack adequate non-invasive biomarkers. consists accumulation excess lipids liver, causing lipotoxicity progress steatohepatitis (NASH), fibrosis, hepatocellular carcinoma. for pathogenesis current interventions management disease, role sirtuins as potential targets are discussed here. In addition, diagnostic non-coding RNAs emerging biomarkers summarized. availability biomarkers, diagnosis tools crucial detection early signs progression NAFLD. This will expedite clinical trials validation therapeutic treatments.

Language: Английский

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Cellular and Molecular Mechanisms Underlying Liver Fibrosis Regression

Cells, Journal Year: 2021, Volume and Issue: 10(10), P. 2759 - 2759

Published: Oct. 15, 2021

Chronic liver injury of different etiologies may result in hepatic fibrosis, a scar formation process consisting altered deposition extracellular matrix. Progression fibrosis can lead to impaired architecture and function, resulting cirrhosis organ failure. Although was previous thought be an irreversible process, recent evidence convincingly demonstrated resolution organs when the cause is removed. In liver, due its high regenerative ability, extent regression reversion normal higher than other tissues, even advanced disease. The mechanisms recapitulated following main points: removal injurious factors causing chronic damage, elimination, or inactivation myofibroblasts (through various cell fates, including apoptosis, senescence, reprogramming), inflammatory response induction anti-inflammatory/restorative pathways, degradation this review, we will discuss major cellular molecular underlying fibrosis/cirrhosis potential therapeutic approaches aimed at reversing fibrogenic process.

Language: Английский

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Bile acids as modulators of gut microbiota composition and function

Gut Microbes, Journal Year: 2023, Volume and Issue: 15(1)

Published: Feb. 5, 2023

Changes in the composition of gut-associated microbial communities are associated with many human illnesses, but factors driving dysbiosis remain incompletely understood. One factor governing microbiota gut is bile. Bile acids shape through their antimicrobial activity and by activating host signaling pathways that maintain homeostasis. Although bile host-derived, functions integrally linked to bacterial metabolism, which shapes intestinal acid pool. Conditions change size or pool can trigger alterations exacerbate inflammation favor infection opportunistic pathogens. Therefore, manipulating might be a promising strategy remediate dysbiosis.

Language: Английский

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Therapeutic targets, novel drugs, and delivery systems for diabetes associated NAFLD and liver fibrosis

Advanced Drug Delivery Reviews, Journal Year: 2021, Volume and Issue: 176, P. 113888 - 113888

Published: July 24, 2021

Language: Английский

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Molecular Basis of Bile Acid-FXR-FGF15/19 Signaling Axis

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(11), P. 6046 - 6046

Published: May 27, 2022

Bile acids (BAs) are a group of amphiphilic molecules consisting rigid steroid core attached to hydroxyl with varying number, position, and orientation, hydrophilic side chain. While BAs act as detergents solubilize lipophilic nutrients in the small intestine during digestion absorption, they also hormones. Farnesoid X receptor (FXR) is nuclear that forms heterodimer retinoid α (RXRα), activated by enterohepatic circulation reabsorbed via transporters ileum colon, plays critical role regulating gene expression involved cholesterol, BA, lipid metabolism liver. The FXR/RXRα exists distal regulates production fibroblast growth factor (FGF) 15/FGF19, hormone traveling activates hepatic FGF 4 (FGFR4)-β-klotho complex metabolism, well those cell proliferation. Agonists for FXR analogs FGF15/19 currently recognized promising therapeutic target metabolic syndrome cholestatic diseases.

Language: Английский

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Bile acid metabolism and signaling in health and disease: molecular mechanisms and therapeutic targets

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: April 25, 2024

Bile acids, once considered mere dietary surfactants, now emerge as critical modulators of macronutrient (lipid, carbohydrate, protein) metabolism and the systemic pro-inflammatory/anti-inflammatory balance. acid signaling pathways play a crucial role in protecting against, or if aberrant, inducing cardiometabolic, inflammatory, neoplastic conditions, strongly influencing health disease. No curative treatment exists for any bile influenced disease, while most promising well-developed therapeutic was recently rejected by FDA. Here, we provide bottom-up approach on mechanistically explaining their biochemistry, physiology, pharmacology at canonical non-canonical receptors. Using this mechanistic model explain how abnormal physiology drives disease pathogenesis, emphasizing ceramide synthesis may serve unifying pathogenic feature cardiometabolic diseases. We an in-depth summary pre-existing receptor modulators, shortcomings, propose solutions they be remedied. Lastly, rationalize novel targets further translational drug discovery future perspectives. Rather than dismissing therapeutics due to recent setbacks, believe that there is immense clinical potential high likelihood success therapeutics.

Language: Английский

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The Gut Microbial Bile Acid Modulation and Its Relevance to Digestive Health and Diseases

Gastroenterology, Journal Year: 2023, Volume and Issue: 164(7), P. 1069 - 1085

Published: Feb. 24, 2023

The human gut microbiome has been linked to numerous digestive disorders, but its metabolic products have much less well characterized, in part due the expense of untargeted metabolomics and lack ability process data. In this review, we focused on rapidly expanding information about bile acid repertoire produced by microbiome, including impacts acids a wide range host physiological processes diseases, discussed role short-chain fatty other important microbiome-derived metabolites. Of particular note is action metabolites throughout body, which impact ranging from obesity aging disorders traditionally thought as diseases nervous system, that are now recognized being strongly influenced it produces. We also highlighted emerging for modifying improve health or treat disease, "engineered native bacteria'' approach takes bacterial strains patient, modifies them alter metabolism, reintroduces them. Taken together, study derived provided insights into pathophysiological processes, substantial potential new approaches diagnostics therapeutics disease of, involving, gastrointestinal tract.

Language: Английский

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FXR agonists in NASH treatment

Journal of Hepatology, Journal Year: 2023, Volume and Issue: 79(5), P. 1317 - 1331

Published: Aug. 9, 2023

The farnesoid X receptor (FXR), a bile acid (BA)-activated nuclear highly expressed in the liver and intestine, regulates expression of genes involved cholesterol homeostasis, hepatic gluconeogenesis, lipogenesis, inflammation fibrosis, addition to controlling intestinal barrier integrity, preventing bacterial translocation maintaining gut microbiota eubiosis. Non-alcoholic steatohepatitis (NASH), an advanced stage non-alcoholic fatty disease, is characterized by steatosis, hepatocyte damage (ballooning) inflammation, leading cirrhosis hepatocellular carcinoma. NASH represents major unmet medical need, but no pharmacological treatments have yet been approved. pleiotropic mechanisms development offer range therapeutic opportunities among them FXR activation has emerged as established target. Various agonists with different physicochemical properties, which can be broadly classified BA derivatives, non-BA-derived steroidal agonists, non-steroidal partial are clinical development. In this review we will summarize key preclinical features most critically evaluate their potential treatment.

Language: Английский

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Environmentally Relevant Concentrations of Microplastic Exposure Cause Cholestasis and Bile Acid Metabolism Dysregulation through a Gut-Liver Loop in Mice

Environmental Science & Technology, Journal Year: 2024, Volume and Issue: 58(4), P. 1832 - 1841

Published: Jan. 17, 2024

The massive production of plastics causes the ubiquitous existence microplastics (MPs) in biota, therefore, posing exposure risks and potential health concerns to human beings. However, exact mechanisms MPs-induced toxicities abnormalities are largely unknown. In this study, we developed a mouse model gavage polystyrene (PS MPs) for 30 days. We found that PS MPs can damage intestinal barrier, accumulate liver tissue, cause injury. intestine both highly associated with bile acid (BA) metabolism. Indeed, dysregulate BA synthesis efflux-related gene expression liver, causing cholestasis. Tandemly, alter ratio primary secondary feces by affecting composition flora. At last, mice's fecal profile, which affects normal Taken together, present study provides robust data on mechanism toxicity disturbance metabolism via 4-step gut-liver loop.

Language: Английский

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Exploring the Multifaceted Landscape of MASLD: A Comprehensive Synthesis of Recent Studies, from Pathophysiology to Organoids and Beyond

Biomedicines, Journal Year: 2024, Volume and Issue: 12(2), P. 397 - 397

Published: Feb. 8, 2024

Non-alcoholic fatty liver disease (NAFLD) is a widespread contributor to chronic globally. A recent consensus on renaming was established, and metabolic dysfunction-associated steatotic disease, MASLD, chosen as the replacement for NAFLD. The disease’s range extends from less severe previously known non-alcoholic (NAFL), more intense steatohepatitis (MASH), (NASH), characterized by inflammation apoptosis. This research project endeavors comprehensively synthesize most studies encompassing wide spectrum of topics such pathophysiology, risk factors, dietary influences, lifestyle management, genetics, epigenetics, therapeutic approaches, prospective trajectory particularly exploring its connection with organoids.

Language: Английский

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