scholarly journals Activation of TAF9 via Danshensu-Induced Upregulation of HDAC1 Expression Alleviates Non-alcoholic Fatty Liver Disease

2021 ◽  
Vol 12 ◽  
Author(s):  
Ruiwen Wang ◽  
Zhecheng Wang ◽  
Ruimin Sun ◽  
Rong Fu ◽  
Yu Sun ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Liver Disease ◽  
Fatty Liver ◽  
Protective Effect ◽  
Fatty Liver Disease ◽  
Cell Model ◽  
Signaling Mechanism ◽  
Alcoholic Fatty Liver

Fatty acid β-oxidation is an essential pathogenic mechanism in nonalcoholic fatty liver disease (NAFLD), and TATA-box binding protein associated factor 9 (TAF9) has been reported to be involved in the regulation of fatty acid β-oxidation. However, the function of TAF9 in NAFLD, as well as the mechanism by which TAF9 is regulated, remains unclear. In this study, we aimed to investigate the signaling mechanism underlying the involvement of TAF9 in NAFLD and the protective effect of the natural phenolic compound Danshensu (DSS) against NAFLD via the HDAC1/TAF9 pathway. An in vivo model of high-fat diet (HFD)-induced NAFLD and a palmitic acid (PA)-treated AML-12 cell model were developed. Pharmacological treatment with DSS significantly increased fatty acid β-oxidation and reduced lipid droplet (LD) accumulation in NAFLD. TAF9 overexpression had the same effects on these processes both in vivo and in vitro. Interestingly, the protective effect of DSS was markedly blocked by TAF9 knockdown. Mechanistically, TAF9 was shown to be deacetylated by HDAC1, which regulates the capacity of TAF9 to mediate fatty acid β-oxidation and LD accumulation during NAFLD. In conclusion, TAF9 is a key regulator in the treatment of NAFLD that acts by increasing fatty acid β-oxidation and reducing LD accumulation, and DSS confers protection against NAFLD through the HDAC1/TAF9 pathway.

scholarly journals Naringin protects against non-alcoholic fatty liver disease by promoting autophagic flux and lipophagy

2021 ◽  
Author(s):  
Lingling Guan ◽  
Lan Guo ◽  
Heng Zhang ◽  
Hao Liu ◽  
Yuan Qiao ◽  
...  
Keyword(s):  
Liver Disease ◽  
Fatty Liver ◽  
Hepatic Steatosis ◽  
Fatty Liver Disease ◽  
Autophagic Flux ◽  
Mechanism Study ◽  
Alcoholic Fatty Liver ◽  
Alcoholic Fatty Liver Disease

Abstract Background and Purpose: The autophagic degradation of lipid droplets (LDs), termed lipophagy, is the main mechanism contributing to lipid consumption in hepatocytes. The identification of effective and safe natural compounds that target lipophagy to eliminate excess lipids may be a potential therapeutic strategy for non-alcoholic fatty liver disease (NAFLD). Here, we investigated the effects of naringin on NAFLD and the underlying mechanism. Experimental Approach: The role of naringin was investigated in mice fed a high-fat diet (HFD) to induce NAFLD, as well as in AML12 cells and primary hepatocytes stimulated by palmitate (PA). Transcription factor EB (TFEB)-knockdown AML12 cells and hepatocyte-specific TFEB-knockout mice were also used for the mechanism study. In vivo and in vitro studies were conducted using transmission electron microscopy, immunofluorescence techniques and western blot analysis. Key Results: We found that naringin treatment effectively relieved HFD-induced hepatic steatosis in mice and inhibited palmitate (PA)-induced lipid accumulation in hepatocytes. The increased p62 and LC3-II levels observed with excess lipid-support autophagosome accumulation and impaired autophagic flux. Treatment with naringin restored TFEB-mediated lysosomal biogenesis, thereby promoting the fusion of autophagosomes and lysosomes, restoring impaired autophagic flux and further inducing lipophagy. However, the knockdown of TFEB in hepatocytes or the hepatocyte-specific knockout of TFEB in mice abrogated naringin-induced lipophagy, which eliminated the therapeutic effect of naringin on hepatic steatosis. Conclusion and Implications: These results demonstrate that TFEB-mediated lysosomal biogenesis and subsequent lipophagy play essential roles in the ability of naringin to mitigate hepatic steatosis and suggest that naringin is a promising drug for treating or relieving NAFLD.

scholarly journals Fuzi-lizhong Decoction Alleviate Nonalcoholic Fatty Liver Disease by Blocking TLR4/MyD88/TRAF6 Signaling Pathway

2021 ◽  
Author(s):  
Ying Zhang ◽  
Jiayao Yang ◽  
Wei Ma ◽  
Hongfeng Yi ◽  
Yan Liao ◽  
...  
Keyword(s):  
Liver Disease ◽  
Blood Glucose ◽  
Fatty Liver ◽  
Total Cholesterol ◽  
Signaling Pathway ◽  
Fatty Liver Disease ◽  
Quantitative Polymerase Chain Reaction ◽  
Alcoholic Fatty Liver

Abstract Background Fuzi-lizhong decoction (FLD) derives from an ancient Chinese Pharmacopoeia and has been used for the clinical treatment for years. The present study aimed to investigate the activities and underlying mechanisms of FLD against non-alcoholic fatty liver disease (NAFLD). Methods In vivo NAFLD in rats was induced by high-fat diet, and in vitro studies were performed on HL-7702 cells treated with oleic and linoleic. Serum levels of total cholesterol (TC), triglyceride (TG) and blood glucose (Glu) were detected using an automatic biochemical analyzer. Expression of IL-2, IL-6 and TNFα were detected by ELISA. Using the Western blot (WB) and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) to measure the levels of TLR4, MyD88 and TRAF6.Results FLD significantly attenuated inflammation and improved collagen accumulation through down-regulating the levels of IL-2, IL-6, TNFα, NF-κB p65 by inhibited the activation of TLR4/MyD88/TRAF6 signaling pathway both in vivo and in vitro. TLR 4 overexpression in NAFLD was decreased by FLD, leading to the markedly down-regulated levels of myeloid differentiation factor 88 (MyD88) and TNF receptor associated factor 6 (TRAF6). In addition, the significant increased levels of total cholesterol (TC), triglyceride (TG) and blood glucose (Glu) in serum and free fatty acid (FFA) in liver were significant reduced by FLD treatment. Conclusions FLD exhibited potent protective effect against NAFLD via TLR4/MyD88/TRAF6 signaling pathway, which might provide a novel insight into the mechanisms of this compound as an anti-inflammatory candidate for the treatment of ALF in the future.

scholarly journals MicroRNA-20a-5p Ameliorates Non-alcoholic Fatty Liver Disease via Inhibiting the Expression of CD36

2020 ◽  
Vol 8 ◽  
Author(s):  
Xin Wang ◽  
Yan Ma ◽  
Long-Yan Yang ◽  
Dong Zhao
Keyword(s):  
Fatty Acid ◽  
Liver Disease ◽  
Fatty Liver ◽  
Fatty Liver Disease ◽  
Lipid Production ◽  
Luciferase Assay ◽  
Alcoholic Fatty Liver ◽  
Primary Mouse ◽  
Alcoholic Fatty Liver Disease

Fatty acid translocase CD36 (CD36) plays an important role in the initiation and pathogenesis of chronic liver disease and non-alcoholic fatty liver disease (NAFLD). The purpose of this study is to investigate the regulation of microRNA-20a-5p (miR-20a-5p) on CD36 in the pathogenesis of NAFLD. Human plasma samples were obtained from NAFLD patients and healthy controls. Mice were fed with high-fat diet to induce an in vivo NAFLD model. Histology staining was performed to examine the morphology and lipid deposition of mouse liver tissue. Real-time PCR, dual-luciferase assay, and western blotting were employed to detect the relationship between miR-20a-5p and CD36. The expression level of miR-20a-5p was decreased in NAFLD patients, HFD mice, and free fatty acid (FFA)-treated HepG2 cells or primary mouse hepatocytes, accompanied by increased lipid production in hepatocytes. MiR-20a-5p suppressed the expression of CD36 to reduce lipid accumulation via binding to its 3’-untranslated region (UTR). However, under the condition of interference with CD36, further inhibition of miR-20a-5p would not cause lipid over-accumulation. In this study, we found that miR-20a-5p played a protective role in lipid metabolic disorders of NAFLD by targeting CD36, which indicated the prospect of miR-20a-5p as a biomarker and treatment target for NAFLD.

scholarly journals Blueberry, combined with probiotics, alleviates non-alcoholic fatty liver diseaseviaIL-22-mediated JAK1/STAT3/BAX signaling

2018 ◽  
Vol 9 (12) ◽  
pp. 6298-6306 ◽  
Author(s):  
Juanjuan Zhu ◽  
Mingyu Zhou ◽  
Xueke Zhao ◽  
Mao Mu ◽  
Mingliang Cheng
Keyword(s):  
Liver Disease ◽  
Fatty Liver ◽  
Fatty Liver Disease ◽  
Alcoholic Fatty Liver ◽  
Alcoholic Fatty Liver Disease

Blueberry, combined with probiotics, improves non-alcoholic fatty liver disease bothin vivoandin vitroby IL-22.

scholarly journals Studying non-alcoholic fatty liver disease: the ins and outs of in vivo, ex vivo and in vitro human models

2018 ◽  
Vol 0 (0) ◽  
Author(s):  
Charlotte J. Green ◽  
Siôn A. Parry ◽  
Pippa J. Gunn ◽  
Carlo D.L. Ceresa ◽  
Fredrik Rosqvist ◽  
...  
Keyword(s):  
Liver Disease ◽  
Fatty Liver ◽  
Fatty Liver Disease ◽  
In Vitro Models ◽  
Ex Situ ◽  
Whole Body ◽  
Alcoholic Fatty Liver ◽  
Alcoholic Fatty Liver Disease

AbstractThe prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing. Determining the pathogenesis and pathophysiology of human NAFLD will allow for evidence-based prevention strategies, and more targeted mechanistic investigations. Various in vivo, ex situ and in vitro models may be utilised to study NAFLD; but all come with their own specific caveats. Here, we review the human-based models and discuss their advantages and limitations in regards to studying the development and progression of NAFLD. Overall, in vivo whole-body human studies are advantageous in that they allow for investigation within the physiological setting, however, limited accessibility to the liver makes direct investigations challenging. Non-invasive imaging techniques are able to somewhat overcome this challenge, whilst the use of stable-isotope tracers enables mechanistic insight to be obtained. Recent technological advances (i.e. normothermic machine perfusion) have opened new opportunities to investigate whole-organ metabolism, thus ex situ livers can be investigated directly. Therefore, investigations that cannot be performed in vivo in humans have the potential to be undertaken. In vitro models offer the ability to perform investigations at a cellular level, aiding in elucidating the molecular mechanisms of NAFLD. However, a number of current models do not closely resemble the human condition and work is ongoing to optimise culturing parameters in order to recapitulate this. In summary, no single model currently provides insight into the development, pathophysiology and progression across the NAFLD spectrum, each experimental model has limitations, which need to be taken into consideration to ensure appropriate conclusions and extrapolation of findings are made.

scholarly journals In Vitro and In Vivo Models of Non-Alcoholic Fatty Liver Disease: A Critical Appraisal

2020 ◽  
Vol 10 (1) ◽  
pp. 36
Author(s):  
Pierre-Antoine Soret ◽  
Julie Magusto ◽  
Chantal Housset ◽  
Jérémie Gautheron
Keyword(s):  
Liver Disease ◽  
Fatty Liver ◽  
Fatty Liver Disease ◽  
Preclinical Research ◽  
In Vivo Models ◽  
Alcoholic Fatty Liver ◽  
Cellular Models ◽  
Alcoholic Fatty Liver Disease

Non-alcoholic fatty liver disease (NAFLD), including non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH), represents the hepatic manifestation of obesity and metabolic syndrome. Due to the spread of the obesity epidemic, NAFLD is becoming the most common chronic liver disease and one of the principal indications for liver transplantation. However, no pharmacological treatment is currently approved to prevent the outbreak of NASH, which leads to fibrosis and cirrhosis. Preclinical research is required to improve our knowledge of NAFLD physiopathology and to identify new therapeutic targets. In the present review, we summarize advances in NAFLD preclinical models from cellular models, including new bioengineered platforms, to in vivo models, with a particular focus on genetic and dietary mouse models. We aim to discuss the advantages and limits of these different models.

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