scholarly journals Therapeutic Opportunities of IL-22 in Non-Alcoholic Fatty Liver Disease: From Molecular Mechanisms to Clinical Applications

Biomedicines ◽  
2021 ◽  
Vol 9 (12) ◽  
pp. 1912
Author(s):  
Wenjing Zai ◽  
Wei Chen ◽  
Hongrui Liu ◽  
Dianwen Ju
Keyword(s):  
Liver Disease ◽  
Fatty Liver ◽  
Targeted Delivery ◽  
Fatty Liver Disease ◽  
Molecular Mechanisms ◽  
Janus Kinase ◽  
Alcoholic Fatty Liver ◽  
Nonalcoholic Fatty Liver ◽  
Interleukin 22 ◽  
Tissue Repair And Regeneration

Nonalcoholic fatty liver disease (NAFLD) represents one of the most common liver disorders and can progress into a series of liver diseases, including nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and even liver cancer. Interleukin-22 (IL-22), a member of the IL-10 family of cytokines, is predominantly produced by lymphocytes but acts exclusively on epithelial cells. IL-22 was proven to favor tissue protection and regeneration in multiple diseases. Emerging evidence suggests that IL-22 plays important protective functions against NAFLD by improving insulin sensitivity, modulating lipid metabolism, relieving oxidative and endoplasmic reticulum (ER) stress, and inhibiting apoptosis. By directly interacting with the heterodimeric IL-10R2 and IL-22R1 receptor complex on hepatocytes, IL-22 activates the Janus kinase 1 (JAK1)/ signal transducer and activator of transcription 3 (STAT3), c-Jun N-terminal kinase (JNK) and extracellular-signal regulated kinase (ERK) pathways to regulate the subsequent expression of genes involved in inflammation, metabolism, tissue repair, and regeneration, thus alleviating hepatitis and steatosis. However, due to the wide biodistribution of the IL-22 receptor and its proinflammatory effects, modifications such as targeted delivery of IL-22 expression and recombinant IL-22 fusion proteins to improve its efficacy while reducing systemic side effects should be taken for further clinical application. In this review, we summarized recent progress in understanding the physiological and pathological importance of the IL-22-IL-22R axis in NAFLD and the mechanisms of IL-22 in the protection of NAFLD and discussed the potential strategies to maneuver this specific cytokine for therapeutic applications for NAFLD.

scholarly journals Emerging Roles of Impaired Autophagy in Fatty Liver Disease and Hepatocellular Carcinoma

2021 ◽  
Vol 2021 ◽  
pp. 1-19
Author(s):  
Suryakant Niture ◽  
Minghui Lin ◽  
Leslimar Rios-Colon ◽  
Qi Qi ◽  
John T. Moore ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Liver Disease ◽  
Fatty Liver ◽  
Fatty Liver Disease ◽  
Molecular Mechanisms ◽  
Alcoholic Fatty Liver ◽  
Nonalcoholic Fatty Liver ◽  
Lipid Catabolism ◽  
Alcoholic Fatty Liver Disease ◽  
Catabolic Process

Autophagy is a conserved catabolic process that eliminates dysfunctional cytosolic biomolecules through vacuole-mediated sequestration and lysosomal degradation. Although the molecular mechanisms that regulate autophagy are not fully understood, recent work indicates that dysfunctional/impaired autophagic functions are associated with the development and progression of nonalcoholic fatty liver disease (NAFLD), alcoholic fatty liver disease (AFLD), and hepatocellular carcinoma (HCC). Autophagy prevents NAFLD and AFLD progression through enhanced lipid catabolism and decreasing hepatic steatosis, which is characterized by the accumulation of triglycerides and increased inflammation. However, as both diseases progress, autophagy can become impaired leading to exacerbation of both pathological conditions and progression into HCC. Due to the significance of impaired autophagy in these diseases, there is increased interest in studying pathways and targets involved in maintaining efficient autophagic functions as potential therapeutic targets. In this review, we summarize how impaired autophagy affects liver function and contributes to NAFLD, AFLD, and HCC progression. We will also explore how recent discoveries could provide novel therapeutic opportunities to effectively treat these diseases.

New therapy for fatty liver

2018 ◽  
Vol 1 (2) ◽  
pp. 24-28
Author(s):  
Tanita Suttichaimongkol
Keyword(s):  
Oxidative Stress ◽  
Liver Disease ◽  
Fatty Liver ◽  
Fatty Liver Disease ◽  
Lifestyle Modifications ◽  
Alcoholic Fatty Liver ◽  
Nonalcoholic Fatty Liver ◽  
Liver Insulin Resistance ◽  
Alcoholic Fatty Liver Disease ◽  
Related Mortality

Non-alcoholic fatty liver disease (NAFLD) is a leading cause of death from liver cirrhosis, endstage liver disease, and hepatocellular carcinoma. It is also associated with increased cardiovasculardisease and cancer related mortality. While lifestyle modifications are the mainstay of treatment,only a proportion of patients are able to make due to difficult to achieve and maintain, and so moretreatment options are required such as pharmacotherapy. This review presents the drugs used inmanaging NAFLD and their pharmacologic targets. Therapies are currently directed towards improvingthe metabolic status of the liver, insulin resistance, cell oxidative stress, apoptosis, inflammation orfibrosis. Several agents are now in large clinical trials and within the next few years, the availability oftherapeutic options for NAFLD will be approved.     Keywords: nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, fibrosis, cirrhosis  

Natural Aldose Reductase Inhibitor: A Potential Therapeutic Agent for Non-alcoholic Fatty Liver Disease

2020 ◽  
Vol 21 (6) ◽  
pp. 599-609 ◽  
Author(s):  
Longxin Qiu ◽  
Chang Guo
Keyword(s):  
Oxidative Stress ◽  
Liver Disease ◽  
Fatty Liver ◽  
Aldose Reductase ◽  
Fatty Liver Disease ◽  
Acid Oxidation ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Alcoholic Fatty Liver ◽  
Nonalcoholic Fatty Liver

Aldose reductase (AR) has been reported to be involved in the development of nonalcoholic fatty liver disease (NAFLD). Hepatic AR is induced under hyperglycemia condition and converts excess glucose to lipogenic fructose, which contributes in part to the accumulation of fat in the liver cells of diabetes rodents. In addition, the hyperglycemia-induced AR or nutrition-induced AR causes suppression of the transcriptional activity of peroxisome proliferator-activated receptor (PPAR) α and reduced lipolysis in the liver, which also contribute to the development of NAFLD. Moreover, AR induction in non-alcoholic steatohepatitis (NASH) may aggravate oxidative stress and the expression of inflammatory cytokines in the liver. Here, we summarize the knowledge on AR inhibitors of plant origin and review the effect of some plant-derived AR inhibitors on NAFLD/NASH in rodents. Natural AR inhibitors may improve NAFLD at least in part through attenuating oxidative stress and inflammatory cytokine expression. Some of the natural AR inhibitors have been reported to attenuate hepatic steatosis through the regulation of PPARα-mediated fatty acid oxidation. In this review, we propose that the natural AR inhibitors are potential therapeutic agents for NAFLD.

Molecular mechanisms of non-alcoholic fatty liver disease development

2021 ◽  
Vol 24 (4) ◽  
pp. 120
Author(s):  
T.S. Sall ◽  
E.S. Shcherbakova ◽  
S.I. Sitkin ◽  
T.Ya. Vakhitov ◽  
I.G. Bakulin ◽  
...  
Keyword(s):  
Liver Disease ◽  
Fatty Liver ◽  
Fatty Liver Disease ◽  
Molecular Mechanisms ◽  
Disease Development ◽  
Alcoholic Fatty Liver ◽  
Alcoholic Fatty Liver Disease

scholarly journals Prevalence and Predictor of Nonalcoholic Steatohepatitis (NASH) in Nonalcoholic Fatty Liver Disease (NAFLD)

2015 ◽  
Vol 32 (2) ◽  
pp. 71-77 ◽  
Author(s):  
Shahinul Alam ◽  
Mahabubul Alam ◽  
Sheikh Mohammad Noor E Alam ◽  
Ziaur Rahman Chowdhury ◽  
Jahangir Kabir
Keyword(s):  
Metabolic Syndrome ◽  
Liver Disease ◽  
Liver Biopsy ◽  
Fatty Liver ◽  
Fatty Liver Disease ◽  
Resistance Index ◽  
Histopathological Study ◽  
Alcoholic Fatty Liver ◽  
Nonalcoholic Fatty Liver ◽  
Alcoholic Fatty Liver Disease

Fatty liver is a common cause of chronic liver disease in developed as well as developing countries.We have designed this study to estimate the prevalence and predictors for non alcoholic steatohepatitis (NASH) in non alcoholic fatty liver disease (NAFLD). We have included 493 patients with sonographic evidence of fatty change in liver and 177 of them had done liver biopsy for histopathological study. Other causes of liver disease and alcohol consumption were excluded. Metabolic syndrome and biochemical and anthropometric evaluation was done. Females were predominating 250 (57.0 %). Centrally obese 422 (96.2 %) was more than over all obesity330 (75.1%). NASH was absent in 10 (5.6%) cases and diagnostic of NASH was 75 Journal of Bangladesh College of Physicians and Surgeons Vol. 32, No. 2, April 2014 (42.4 %).Presence of diabetes could significantly (p = 0.001) predicted NASH. Age, sex, BMI, waist circumference, Serum HDL,triglyceride, insulin resistance index, hypertension, metabolic syndrome could not predict NASH. Serum GGT level was significantly (p = 0.05) higher in NASHwith a sensitivity of 45 % and specificity of 68 % only. Serum ALT and AST level could not detect NASH. Females were predominant sufferer of NAFLD in Bangladesh. Prevalence of NASH was much higher42.4%. Diabetes was the main predictor of NASH. GGT was the only biochemical indicator of NASH. We recommend liver biopsy in NAFLD with diabetes and raised GGT.J Bangladesh Coll Phys Surg 2014; 32: 71-77

scholarly journals Sex Dimorphism of Nonalcoholic Fatty Liver Disease (NAFLD) in Pparg-Null Mice

2021 ◽  
Vol 22 (18) ◽  
pp. 9969
Author(s):  
Mariano Schiffrin ◽  
Carine Winkler ◽  
Laure Quignodon ◽  
Aurélien Naldi ◽  
Martin Trötzmüller ◽  
...  
Keyword(s):  
Gene Expression ◽  
Liver Disease ◽  
Fatty Liver ◽  
Nonalcoholic Fatty Liver Disease ◽  
Fatty Liver Disease ◽  
Molecular Mechanisms ◽  
Liver Steatosis ◽  
Whole Body ◽  
Sex Dimorphism ◽  
Nonalcoholic Fatty Liver

Men with nonalcoholic fatty liver disease (NAFLD) are more exposed to nonalcoholic steatohepatitis (NASH) and liver fibrosis than women. However, the underlying molecular mechanisms of NALFD sex dimorphism are unclear. We combined gene expression, histological and lipidomic analyses to systematically compare male and female liver steatosis. We characterized hepatosteatosis in three independent mouse models of NAFLD, ob/ob and lipodystrophic fat-specific (PpargFΔ/Δ) and whole-body PPARγ-null (PpargΔ/Δ) mice. We identified a clear sex dimorphism occurring only in PpargΔ/Δ mice, with females showing macro- and microvesicular hepatosteatosis throughout their entire life, while males had fewer lipid droplets starting from 20 weeks. This sex dimorphism in hepatosteatosis was lost in gonadectomized PpargΔ/Δ mice. Lipidomics revealed hepatic accumulation of short and highly saturated TGs in females, while TGs were enriched in long and unsaturated hydrocarbon chains in males. Strikingly, sex-biased genes were particularly perturbed in both sexes, affecting lipid metabolism, drug metabolism, inflammatory and cellular stress response pathways. Most importantly, we found that the expression of key sex-biased genes was severely affected in all the NAFLD models we tested. Thus, hepatosteatosis strongly affects hepatic sex-biased gene expression. With NAFLD increasing in prevalence, this emphasizes the urgent need to specifically address the consequences of this deregulation in humans.

scholarly journals 5-Bis-(2,6-difluoro-benzylidene) Cyclopentanone Acts as a Selective 11β-Hydroxysteroid Dehydrogenase one Inhibitor to Treat Diet-Induced Nonalcoholic Fatty Liver Disease in Mice

2021 ◽  
Vol 12 ◽  
Author(s):  
Hongguo Guan ◽  
Yiyan Wang ◽  
Huitao Li ◽  
Qiqi Zhu ◽  
Xiaoheng Li ◽  
...  
Keyword(s):  
Liver Disease ◽  
Fatty Liver ◽  
Nonalcoholic Fatty Liver Disease ◽  
Fatty Liver Disease ◽  
Serum Insulin ◽  
Hydroxysteroid Dehydrogenase ◽  
Biologically Active ◽  
Alcoholic Fatty Liver ◽  
Nonalcoholic Fatty Liver ◽  
Low Concentration

Background: 11β-Hydroxysteroid dehydrogenase one is responsible for activating inert glucocorticoid cortisone into biologically active cortisol in humans and may be a novel target for the treatment of nonalcoholic fatty liver disease.Methods: A series of benzylidene cyclopentanone derivatives were synthesized, and the selective inhibitory effects on rat, mouse and human 11β-hydroxysteroid dehydrogenase one and two were screened. The most potent compound [5-bis-(2,6-difluoro-benzylidene)-cyclopentanone] (WZS08), was used to treat nonalcoholic fatty liver disease in mice fed a high-fat-diet for 100 days.Results: WZS08 was the most potent inhibitor of rat, mouse, and human 11β-hydroxysteroid dehydrogenase 1, with half maximum inhibitory concentrations of 378.0, 244.1, and 621.1 nM, respectively, and it did not affect 11β-hydroxysteroid dehydrogenase two at 100 μM. When mice were fed WZS08 (1, 2, and 4 mg/kg) for 100 days, WZS08 significantly lowered the serum insulin levels and insulin index at 4 mg/kg. WZS08 significantly reduced the levels of serum triglycerides, cholesterol, low-density lipoprotein, and hepatic fat ratio at low concentration of 1 mg/kg. It down-regulated Plin2 expression and up-regulated Fabp4 expression at low concentration of 1 mg/kg. It significantly improved the morphology of the non-alcoholic fatty liver.Conclusion: WZS08 selectively inhibits rat, mouse, and human 11β-hydroxysteroid dehydrogenase 1, and can treat non-alcoholic fatty liver disease in a mouse model.

Is liver fat detrimental to vessels?: intersections in the pathogenesis of NAFLD and atherosclerosis

2008 ◽  
Vol 115 (1) ◽  
pp. 1-12 ◽  
Author(s):  
Paola Loria ◽  
Amedeo Lonardo ◽  
Giovanni Targher
Keyword(s):  
Liver Disease ◽  
Fatty Liver ◽  
Fatty Liver Disease ◽  
Molecular Mechanisms ◽  
Treatment Strategies ◽  
Liver Fat ◽  
Cvd Risk ◽  
Alcoholic Fatty Liver ◽  
Insulin Resistant ◽  
Major Player

NAFLD (non-alcoholic fatty liver disease) encompasses the spectrum of fatty liver disease in insulin-resistant individuals who often display T2DM (Type 2 diabetes mellitus) and obesity. The present review highlights the pathophysiological basis and clinical evidence for a possible causal linkage between NAFLD and CVD (cardiovascular disease). The role of traditional and non-traditional CVD risk factors in the pathophysiology of NAFLD is considered in the first part of the review, with the basic science shared by atherogenesis and hepatic steatogenesis discussed in depth in the second part. In conclusion, NAFLD is not an innocent bystander, but a major player in the development and progression of CVD. NAFLD and CVD also share similar molecular mechanisms and targeted treatment strategies. On the research side, studies should focus on interventions aimed at restoring energy homoeostasis in lipotoxic tissues and at improving hepatic (micro)vascular blood supply.

Abstract 454: High Density Lipoprotein Proteome Dynamics is Altered in Non-alcoholic Fatty Liver Disease

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Takhar Kasumov
Keyword(s):  
Liver Disease ◽  
Fatty Liver ◽  
Oxidase Activity ◽  
Fatty Liver Disease ◽  
Metabolic Labeling ◽  
Alcoholic Fatty Liver ◽  
Nonalcoholic Fatty Liver ◽  
Inflammatory Index ◽  
Complement 3 ◽  
Hdl Dysfunction

Objectives: Nonalcoholic fatty liver disease (NAFLD) is associated with an increased rate of cardiovascular disease (CVD) related mortality. HDL protects against CVD through reverse cholesterol transport, anti-oxidant and anti-inflammatory functions. HDL functions and the proteome composition are altered in CVD. We used 2 H 2 O metabolic labeling approach to test hypothesis that altered HDL proteome dynamics is involved in HDL dysfunction in NAFLD. Methods: The kinetics of HDL proteins were measured in patients NAFLD (n=12) and healthy controls (n=8). Each subject consumed 2 H 2 O in their drinking water and blood samples were collected at different time points during one week. 2 H-enrichment of tryptic peptides from HDL proteins were analyzed by mass spectrometry. Oxidase activity of HDL-associated ceruloplasmin (Cp) and HDL’s inflammatory index were quantified using spectrophotometric assays. Results: Compared to control, NAFLD had higher BMI, Hba1c, HOMA-IR, plasma AST, ALT and triglycerides, but similar LDL and HDL cholesterol. NAFLD also had higher inflammatory index (1.8±0.5 vs 1.2±0.2 RUF/mgHDLc/min, p<0.05) and oxidase activity of Cp (93.7±61.2 vs 61.2 U/L, p<0.005). This was associated with increased serum actvity of MPO (6.2±1.2 vs 8.4±1.6, p<0.05), a nutrophile-derived protein involved in HDL dysfunction. HDL NAFLD was significantly enriched with proteins involved in the acute phase response (complement 3, Cp) but depleted in apoAII and PON1. These changes were associated with increased fractional catabolic rates (FCRs) of apoAI (1.6±0.2 vs 1.1±0.3 %/h), apoAII (1.6±0.2 vs 1.1±0.3 %/h), apoAIV (2.6±0.8 vs 3.9±0.7%/h) and increased relative production rate (RPR) of complement 3 (>4 fold). Oxidase activity of Cp was positively associated with FCR of apoAI (r=0.53, p=0.002) and RPR of C3 (r=0.32, p=0.03). Conclusions: HDL dysfunction in NASH could be related to the altered turnover of HDL proteins, including increased degradation of apoAI, apoAII, apoAIV and increased production of C3.

Potential Natural Compounds for the Prevention and Treatment of Nonalcoholic Fatty Liver Disease: A Review on Molecular Mechanisms

2021 ◽  
Vol 15 ◽  
Author(s):  
Cheng Ma ◽  
Cheng Wang ◽  
Yafang Zhang ◽  
Honglin Zhou ◽  
Yunxia Li
Keyword(s):  
Liver Disease ◽  
Chinese Medicine ◽  
Traditional Chinese Medicine ◽  
Fatty Liver ◽  
Nonalcoholic Fatty Liver Disease ◽  
Fatty Liver Disease ◽  
Molecular Mechanisms ◽  
Natural Compounds ◽  
Nonalcoholic Fatty Liver ◽  
Prevention And Treatment

Background: Nonalcoholic fatty liver disease (NAFLD) is a kind of metabolic stress-induced liver injury closely related to insulin resistance and genetic susceptibility, and there is no specific drug for its clinical treatment currently. In recent years, a large amount of literature has reported that many natural compounds extracted from traditional Chinese medicine (TCM) can improve NAFLD through various mechanisms. According to the latest reports, some emerging natural compounds have shown great potential to improve NAFLD but are seldom used clinically due to the lacking special research. Purpose: This paper aims to summarize the molecular mechanisms of the potential natural compounds on improving NAFLD, thus providing a direction and basis for further research on the pathogenesis of NAFLD and the development of effective drugs for the prevention and treatment of NAFLD. Methods: By searching various online databases, such as Web of Science, SciFinder, PubMed, and CNKI, NAFLD and these natural compounds were used as the keywords for detailed literature retrieval. Results: The pathogenesis of NAFLD and the molecular mechanisms of the potential natural compounds on improving NAFLD have been reviewed. Conclusion: Many natural compounds from traditional Chinese medicine have a good prospect in the treatment of NAFLD, which can serve as a direction for the development of anti-NAFLD drugs in the future.

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