Roles of the peroxisome proliferator-activated receptors (PPARs) in the pathogenesis of nonalcoholic fatty liver disease (NAFLD)

Pharmacological Research, Год журнала: 2023, Номер 192, С. 106786 - 106786

Опубликована: Май 3, 2023

Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum of phenotypes which start with simple steatosis and lipid accumulation in the hepatocytes - typical histological lesions characteristic. It may progress to non-alcoholic steatohepatitis (NASH) that is characterized by hepatic inflammation and/or fibrosis subsequent onset NAFLD-related cirrhosis hepatocellular carcinoma (HCC). Due central role metabolism, NAFLD regarded as result contribution metabolic abnormalities seen syndrome. Peroxisome proliferator-activated receptors (PPARs) has three subtypes, govern expression genes responsible for energy cellular development, inflammation, differentiation. The agonists PPARα, such fenofibrate clofibrate, have been used lipid-lowering drugs clinical practice. Thiazolidinediones (TZDs) ligands PPARγ, rosiglitazone pioglitazone, are also treatment type 2 diabetes (T2D) insulin resistance (IR). Increasing evidence suggests PPARβ/δ potential therapeutic effects improving sensitivity metabolism disorders. In addition, PPARs considered hypertension, atherosclerosis (AS) or diabetic nephropathy. Their crucial biological roles dictate significance PPARs-targeting medical research drug discovery. Here, it reviews activities, ligand selectivity functions family, discusses relationship between pathogenesis This will open new possibilities application medicine, provide idea related diseases.

Язык: Английский

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Geographical similarity and differences in the burden and genetic predisposition of NAFLD

Hepatology, Год журнала: 2022, Номер 77(4), С. 1404 - 1427

Опубликована: Сен. 5, 2022

NAFLD has become a major public health problem for more than 2 decades with growing prevalence in parallel the epidemic of obesity and type diabetes (T2D). The disease burden differs across geographical regions ethnicities. Variations metabolic diseases, extent urban–rural divide, dietary habits, lifestyles, risk protective alleles can contribute to such differences. rise led remarkable increase number cases cirrhosis, hepatocellular carcinoma, hepatic decompensation, liver‐related mortality related NAFLD. Moreover, is associated multiple extrahepatic manifestations. Most them are factors progression liver fibrosis thus worsen prognosis All these comorbidities complications affect quality life subjects Given huge size population NAFLD, it expected that patients, healthcare systems, economy will suffer from ongoing In this review, we examine areas ethnicities, together distribution some well‐known genetic variants We also describe special populations including patients T2D, lean pediatric population, concomitant diseases. discuss outcomes, patient‐reported economic

Язык: Английский

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Epidemiology of Metabolic Dysfunction Associated Steatotic Liver Disease

Clinical and Molecular Hepatology, Год журнала: 2024, Номер unknown

Опубликована: Авг. 19, 2024

As the rates of obesity and type 2 diabetes (T2D) continue to increase globally, so does prevalence metabolic dysfunction associated steatotic liver disease (MASLD). Currently, 38% all adults 7-14% children adolescents have MASLD. By 2040, MASLD rate for is projected over 55%. Although many with will not develop progressive disease, given vast number patients MASLD, it has now become top indication transplant in United States those hepatocellular carcinoma (HCC) women. However, most common cause mortality among remains death cardiovascular diseases. In addition outcomes (cirrhosis HCC), increased risk developing de-novo T2D, chronic kidney sarcopenia extrahepatic cancers. Furthermore, decreased health related quality life, work productivity, fatigue healthcare resource utilization substantial economic burden. Similar other lifestyle interventions heathy diet physical activity remain cornerstone managing these patients. a T2D drugs are available treat co-morbid Resmetirom only MASH-targeted medication that was recently approved by Federal Drug Administration use stage 2-3 fibrosis. The following review provides an overview epidemiology, its factors demonstrates without further global initiatives, may increase.

Язык: Английский

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Global, Regional, and National Prevalence of Gout From 1990 to 2019: Age-Period-Cohort Analysis With Future Burden Prediction

JMIR Public Health and Surveillance, Год журнала: 2023, Номер 9, С. e45943 - e45943

Опубликована: Июнь 7, 2023

Background Gout is a common and debilitating condition that associated with significant morbidity mortality. Despite advances in medical treatment, the global burden of gout continues to increase, particularly high–sociodemographic index (SDI) regions. Objective To address aforementioned issue, we used age-period-cohort (APC) modeling analyze trends incidence prevalence from 1990 2019. Methods Data were extracted Global Burden Disease Study 2019 assess all-age age-standardized rates, as well years lived disability for 204 countries territories. APC effects also examined relation prevalence. Future prediction was carried out using Nordpred future cases Bayesian model. Results The has increased by 63.44% over past 2 decades, corresponding increase 51.12% disability. sex ratio remained consistent at 3:1 (male female), but both sexes time. Notably, highest high-SDI regions (95% uncertainty interval 14.19-20.62), growth rate 94.3%. increases steadily age, rapidly quantiles period effect. Finally, cohort effect showed steadily, risk increasing younger birth cohorts. model suggests will continue globally. Conclusions Our study provides important insights into highlights need effective management prophylaxis this condition. our analysis novel approach understanding complex incidence, findings can inform development targeted interventions growing health issue.

Язык: Английский

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Dysfunction of autophagy in high-fat diet-induced non-alcoholic fatty liver disease

Autophagy, Год журнала: 2023, Номер 20(2), С. 221 - 241

Опубликована: Сен. 12, 2023

Non-alcoholic fatty liver disease (NAFLD) is one of the most common chronic diseases with a global rising prevalence, which closely associated high-fat diet (HFD) intake. Macroautophagy/autophagy an evolutionarily conserved degradation process for cytosolic macromolecules and damaged organelles. The potential role autophagy in hepatic lipid metabolism has been recognized, while dysfunction found to contribute NAFLD. Herein, we provide overview phases regulatory machinery, current understanding its protective HFD-induced We also discuss genetic pharmacological interventions that may help elucidate molecular mechanisms influence future therapeutic direction

Язык: Английский

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Melatonin Ameliorates Hepatic Ferroptosis in NAFLD by Inhibiting ER Stress via the MT2/cAMP/PKA/IRE1 Signaling Pathway

International Journal of Biological Sciences, Год журнала: 2023, Номер 19(12), С. 3937 - 3950

Опубликована: Янв. 1, 2023

Ferroptosis, an iron-dependent cell death form, has recently been observed in the development of non-alcoholic fatty liver disease (NAFLD).Melatonin (Mel) shows potential benefits for preventing and treating diseases.Whether how Mel ameliorates hepatic ferroptosis NAFLD is not fully understood.Here we established a mouse model induced by long-term high-fat diet (HFD) feeding.We found that treatment ameliorated global metabolic abnormalities inhibited progression mice.Most importantly, supplementation significantly improved HFD-induced iron homeostasis disorders liver, including overload ferritin transport disorders.For another, lipid peroxidation.The recuperative role exogenous on hepatocyte was also PA-or Erastin-treated HepG2 cells.Mechanistically, MT2, but MT1, involved effect Mel.Furthermore, HFD or Erastin-activated ER stress activated PKA/IRE1 signaling pathway.Co-expression p-PKA p-IRE1 enhanced MT2 antagonist.Inhibitions PKA IRE1 respectively ferroptosis, activations cAMP/PKA reversed Mel's ferroptosis.Collectively, these findings suggest inhibits ameliorating through MT2/cAMP/PKA/IRE1 pathway, proving promising candidate drug NAFLD.

Язык: Английский

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Salvianolic acid B attenuates liver fibrosis by targeting Ecm1 and inhibiting hepatocyte ferroptosis

Redox Biology, Год журнала: 2024, Номер 69, С. 103029 - 103029

Опубликована: Янв. 4, 2024

Hepatocyte ferroptosis promotes the pathogenesis and progression of liver fibrosis. Salvianolic acid B (Sal B) exerts antifibrotic effects. However, pharmacological mechanism target has not yet been fully elucidated. In this study, fibrosis was induced by CCl4 in wild-type mice hepatocyte-specific extracellular matrix protein 1 (Ecm1)-deficient mice, which were separately treated with Sal B, ferrostatin-1, sorafenib or cilengitide. Erastin- CCl4-induced hepatocyte models without Ecm1 gene knockdown evaluated vitro. Subsequently, interaction between xCT binding kinetics determined. We found that significantly attenuated mice. deletion hepatocytes abolished effect B. Mechanistically, protected against upregulating Ecm1. Further research revealed as a direct for treating Interestingly, interacted to regulate ferroptosis. vitro treatment, abrogated after LO2 cells. Therefore, alleviates targeting up-regulation inhibiting The regulates

Язык: Английский

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TRIM56 protects against nonalcoholic fatty liver disease by promoting the degradation of fatty acid synthase

Journal of Clinical Investigation, Год журнала: 2024, Номер 134(5)

Опубликована: Янв. 11, 2024

Nonalcoholic liver disease (NAFLD) encompasses a continuum from simple steatosis, to non-alcoholic steatohepatitis (NASH). However, there are currently no approved pharmacotherapies for NAFLD although several drugs in advanced stages of clinical development. Because the complex pathophysiology and heterogeneity NALFD, identification potential therapeutic targets is clinically important. Here, we demonstrated that TRIM56 protein abundance markedly downregulated livers individuals with mice fed high-fat diet. Hepatocyte-specific ablation exacerbated progression NAFLD, while hepatic overexpression suppressed it. Integrative analyses interactomic transcriptomic profiling revealed pivotal role lipid metabolism identified lipogenesis factor FASN as direct binding partner TRIM56. directly interacts triggers its K48-linked ubiquitination-dependent degradation. Finally, by using AI-based virtual screening, discovered an orally bioavailable small-molecule inhibitor (named FASstatin) which potentiates TRIM56-mediated ubiquitination. Therapeutic administration FASstatin improved NASH pathologies optimal safety, tolerability pharmacokinetic profile. Our findings provide proof-of-concept targeting TRIM56/FASN axis hepatocytes may offer avenues treat NAFLD.

Язык: Английский

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The global burden of fatty liver disease: the major impact of China

HepatoBiliary Surgery and Nutrition, Год журнала: 2024, Номер 13(1), С. 119 - 123

Опубликована: Янв. 19, 2024

Язык: Английский

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Guideline for the Prevention and Treatment of Metabolic Dysfunction-associated Fatty Liver Disease (Version 2024)

Journal of Clinical and Translational Hepatology, Год журнала: 2024, Номер 000(000), С. 000 - 000

Опубликована: Ноя. 4, 2024

With the rising epidemic of obesity, metabolic syndrome, and type 2 diabetes mellitus in China, dysfunction-associated non-alcoholic fatty liver disease has become most prevalent chronic disease. This condition frequently occurs Chinese patients with alcoholic hepatitis B. To address impending public health crisis its underlying issues, Society Hepatology Medical Association convened a panel clinical experts to revise update "Guideline prevention treatment (2018, China)". The new edition, titled for (Version 2024)", offers comprehensive recommendations on key including screening monitoring, diagnosis evaluation, treatment, follow-up steatotic Metabolic is now preferred English term used interchangeably Additionally, guideline emphasizes importance multidisciplinary collaboration among hepatologists other specialists manage cardiometabolic disorders effectively.

Язык: Английский

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