scholarly journals The Mechanism of Increased Intestinal Palmitic Acids Absorption and The Impact On Hepatic Stellate Cell Activation in Non-Alcoholic Steatohepatitis

2021 ◽  
Author(s):  
Masakazu Hanayama ◽  
Yasunori Yamamoto ◽  
Hiroki Utsunomiya ◽  
Osamu Yoshida ◽  
Liu Shuang ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Portal Vein ◽  
Intestinal Absorption ◽  
Stellate Cell ◽  
Mrna Levels ◽  
Alcoholic Fatty Liver ◽  
Nash Model ◽  
Alcoholic Steatohepatitis ◽  
The Impact ◽  
Palmitic Acids

Abstract Dietary palmitic acids (PAs) promote liver fibrosis in patients with non-alcoholic steatohepatitis (NASH). This study aimed to clarify the intestinal absorption kinetics of dietary PAs and the effect of trans-portal PAs on the activation of hepatic stellate cells (HSCs) involved in liver fibrosis in patients with NASH. First, we found that the concentration of blood PAs after meals was significantly increased in NASH patients compared to control patients (P < 0.01). Second, gene expressions associated with fat absorption and chylomicron formation, such as CD36 and MTP, were significantly increased in the intestine of the NASH model rats fed a high-fat-cholesterol diet compared to control rats. Furthermore, portal PA levels after meals in the NASH model rats were significantly higher compared to control and non-alcoholic fatty liver (NAFL) rats (P<0.01). Third, PA injection via the portal vein to the liver in control rats increased the mRNA levels associated with the activation of HSCs and the expression of α-SMA in liver tissues. Our study showed an increased intestinal absorption of dietary-derived PA in NASH. The rapid increase in PAs via the portal vein to the liver may activate HSCs and affect the development of liver fibrosis in NASH.

scholarly journals The mechanism of increased intestinal palmitic acid absorption and its impact on hepatic stellate cell activation in nonalcoholic steatohepatitis

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Masakazu Hanayama ◽  
Yasunori Yamamoto ◽  
Hiroki Utsunomiya ◽  
Osamu Yoshida ◽  
Shuang Liu ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Portal Vein ◽  
Palmitic Acid ◽  
Intestinal Absorption ◽  
Nonalcoholic Steatohepatitis ◽  
Cell Activation ◽  
Stellate Cell ◽  
Mrna Levels ◽  
Nonalcoholic Fatty Liver ◽  
Chylomicron Formation

AbstractDietary palmitic acid (PA) promotes liver fibrosis in patients with nonalcoholic steatohepatitis (NASH). Herein, we clarified the intestinal absorption kinetics of dietary PA and effect of trans-portal PA on the activation of hepatic stellate cells (HSCs) involved in liver fibrosis in NASH. Blood PA levels after meals were significantly increased in patients with NASH compared to those in the control. Expression of genes associated with fat absorption and chylomicron formation, such as CD36 and MTP, was significantly increased in the intestine of NASH model rats compared with that in the controls. Plasma levels of glucagon-like peptide-2, involved in the upregulation of CD36 expression, were elevated in NASH rats compared with those in the controls. Furthermore, portal PA levels after meals in NASH rats were significantly higher than those in control and nonalcoholic fatty liver rats. Moreover, PA injection into the portal vein to the liver in control rats increased the mRNA levels associated with the activation of HSCs. Increased intestinal absorption of diet-derived PA was observed in NASH. Thus, the rapid increase in PA levels via the portal vein to the liver may activate HSCs and affect the development of liver fibrosis in NASH.

scholarly journals Hepatoprotective effect of Qushihuayu formula on non-alcoholic steatohepatitis induced by MCD diet in rat

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Qingping Lan ◽  
Zhitao Ren ◽  
Yan Chen ◽  
Guozhen Cui ◽  
I. Cheong Choi ◽  
...  
Keyword(s):  
Stellate Cell ◽  
Diet Group ◽  
Hepatoprotective Effect ◽  
Mrna Levels ◽  
Model Group ◽  
Alcoholic Fatty Liver ◽  
Alcoholic Steatohepatitis ◽  
Mapk Pathways ◽  
Ppar Γ ◽  
Pre Treatment

Abstract Background Non-alcoholic steatohepatitis (NASH) is an advanced form of non-alcoholic fatty liver disease (NAFLD) for which there is yet any standard pharmacotherapy. Traditional Chinese medicine formula such as Qushihuayu (QSHY) composing of multiple bioactive compounds has been used to treat NAFLD and NASH and shows beneficial effects over single compound treatment. This study aimed to investigate the mechanism of hepatoprotective effect of QSHY formula using a rat model. Methods Six-weeks old male Wistar rats were given methionine/choline supplemented (MCS) diet for 8 weeks and used as the blank control. Another 7 rats, which received methionine/choline deficient (MCD) diet in the first 6 weeks and a MCS&MCD (1:1) mixture diet in the last 2 weeks, were used as the model group. The groups of QSHY pre-treatment, low dosage, medium dosage and high dosage were given the same diet as the model group. Except for pre-treatment group (1 week in advanced of other groups), all QSHY treatment groups received QSHY formula by gavage every day since the MCD diet started. Results In the MCD diet group, the QSHY formula decreased the serum ALT and AST levels, lipid droplets, inflammation foci, FAS and α-SMA protein expression than MCD diet group. MAPK pathways phospharylation were markedly depressed by the QSHY formula. Moreover, QSHY formula enhanced PPAR-γ and p-p65 translocating into nucleus. The administration of QSHY increased hepatic mRNA levels of Transcription Factor 1 alpha (HNF1A), Hepatocyte Nuclear Factor 4 alpha (HNF4A) and Forkhead box protein A3 (FOXA3) which play a pivotal role in Hepatic stellate cell (HSCs) reprogramming. Conclusion These findings suggest that QSHY formula exerts a hepatoprotective effect against steatosis and fibrosis presumably via depressed MAPK pathways phosphorylation, reinforcement of PPAR-γ and p-p65 translocating into nucleus and enhanced HSCs reprogramming.

scholarly journals Sestrin 2 Attenuates Rat Hepatic Stellate Cell (HSC) Activation and Liver Fibrosis via an mTOR/AMPK-Dependent Mechanism

2018 ◽  
Vol 51 (5) ◽  
pp. 2111-2122 ◽  
Author(s):  
Yi-Bing Hu ◽  
Xiao-Ting Ye ◽  
Qing-Qing Zhou ◽  
Rong-Quan Fu
Keyword(s):  
Liver Fibrosis ◽  
Protein Expression ◽  
Hepatic Fibrosis ◽  
Transforming Growth Factor ◽  
Histopathological Examination ◽  
Stellate Cell ◽  
Smooth Muscle Actin ◽  
Mrna Levels ◽  
Alpha Smooth Muscle Actin

Background/Aims: Sestrin 2 is associated with the pathophysiology of several diseases. The aim of this study was to investigate the effects and potential mechanisms of Sestrin 2 in rat hepatic stellate cells (HSCs) during liver fibrogenesis. Methods: In this study, Sestrin 2 protein expression was detected in rat HSC-T6 cells challenged with transforming growth factor-β (TGF-β) and in mice treated with carbon tetrachloride (CCl4), a well-known model of hepatic fibrosis. Next, HSC-T6 cells and fibrotic mice were transfected with lentivirus. The mRNA expression levels of markers of liver fibrosis [alpha-smooth muscle actin (α-SMA) and collagen 1A1 (Col1A1)] were analyzed by quantitative reverse transcription–polymerase chain reaction (RT-PCR). Cell death and proliferation were evaluated by the MTT assay, and biochemical markers of liver damage in serum [alanine transaminase (ALT) and aspartate transaminase (AST)] were also measured using a biochemical analyzer. Histopathological examination was used to evaluate the degree of liver fibrosis, and protein expression [phospho-adenosine monophosphate-activated protein kinase (p-AMPK), AMPK, phospho-mammalian target of rapamycin (p-mTOR), and mTOR] was determined by western blotting. Results: We found that Sestrin 2 was elevated in both the HSC-T6 cell and hepatic fibrosis models. In vitro, overexpression of Sestrin 2 attenuated the mRNA levels of α-SMA and Col1A1, suppressed α-SMA protein expression, and modulated HSC-T6 cell proliferation. In vivo, overexpression of Sestrin 2 reduced the ALT and AST levels as well as the α-SMA and Col1A1 protein expression in the CCl4 model of liver fibrosis. Moreover, the degree of liver fibrosis was ameliorated. Interestingly, overexpression of Sestrin 2 increased p-AMPK but decreased p-mTOR protein expression. Conclusion: Our findings indicate that Sestrin 2 may attenuate the activation of HSCs and ameliorate liver fibrosis, most likely via upregulation of AMPK phosphorylation and suppression of the mTOR signaling pathway.

scholarly journals LncRNA NEAT1/microRNA-129-5p/SOCS2 axis regulates liver fibrosis in alcoholic steatohepatitis

2020 ◽  
Vol 18 (1) ◽  
Author(s):  
Junfeng Ye ◽  
Yuanqiang Lin ◽  
Ying Yu ◽  
Di Sun
Keyword(s):  
Liver Fibrosis ◽  
Liver Function ◽  
Inflammatory Factors ◽  
Cytokine Signaling ◽  
Alcoholic Fatty Liver ◽  
Alcoholic Steatohepatitis ◽  
Inflammation Reaction

Abstract Background Long non-coding RNA nuclear paraspeckle assembly transcript 1 (NEAT1) has been reported to play an essential role in non-alcoholic fatty liver disease. However, the role of NEAT1 in regulation of alcoholic steatohepatitis (ASH) remains largely unknown. This study aims to explore the role of NEAT1 in ASH by mediating microRNA-129-5p (miR-129-5p) targeting suppressor of cytokine signaling 2 (SOCS2). Methods NEAT1, miR-129-5p and SOCS2 expression in serum of ASH patients were assessed. In the in vitro cellular experiment, we transfected siRNAs, oligonucleotides or plasmids into ethanol-induced AML-12 mouse hepatocytes to alter NEAT1 and miR-129-5p expression, and inflammatory factors and lipid content were determined. In the in vivo animal experiment, we injected lentiviruses carrying siRNAs, oligonucleotides or plasmids onto ASH mice (ASH induced by feeding mice a Lieber-DeCarli ethanol diet) to alter NEAT1 and miR-129-5p expression through the tail vein. Serum liver function, blood lipids and inflammatory factors were detected; liver histopathology, liver cell apoptosis, and fibrosis were observed. The relationship between NEAT1 and miR-129-5p, or between miR-129-5p and SOCS2 was verified. Results MiR-129-5p was reduced while NEAT1 and SOCS2 were elevated in ASH. Inhibited NEAT1 or elevated miR-129-5p suppressed the elevated lipid metabolism and restrained inflammation reaction in ethanol-stimulated AML-12 cells. The promoted miR-129-5p and inhibited NEAT1 could improve the liver function and repress blood lipid, inflammation reaction, hepatocyte apoptosis and liver fibrosis in ethanol-induced ASH mice. Furthermore, NEAT1 could negatively regulate miR-129-5p to target SOCS2. Conclusion We have found that the inhibited NEAT1 could suppress liver fibrosis in ASH mice by promoting miR-129-5p and restraining SOCS2, thereby decelerating the development of ASH.

scholarly journals The miRFIB-Score: A Serological miRNA-Based Scoring Algorithm for the Diagnosis of Significant Liver Fibrosis

Cells ◽  
2019 ◽  
Vol 8 (9) ◽  
pp. 1003 ◽  
Author(s):  
Lambrecht ◽  
Verhulst ◽  
Reynaert ◽  
van Grunsven
Keyword(s):  
Liver Fibrosis ◽  
Stellate Cell ◽  
Early Stage ◽  
Liver Stiffness ◽  
Diagnostic Tools ◽  
Circulating Mirnas ◽  
Alcoholic Fatty Liver ◽  
Chronic Alcohol Abuse ◽  
Significant Liver Fibrosis

Background: The current diagnosis of early-stage liver fibrosis often relies on a serological or imaging-based evaluation of the stage of fibrosis, sometimes followed by an invasive liver biopsy procedure. Novel non-invasive experimental diagnostic tools are often based on markers of hepatocyte damage, or changes in liver stiffness and architecture, which are late-stage characteristics of fibrosis progression, making them unsuitable for the diagnosis of early-stage liver fibrosis. miRNAs control hepatic stellate cell (HSC) activation and are proposed as relevant diagnostic markers. Methods: We investigated the possibility of circulating miRNAs, which we found to be dysregulated upon HSC activation, to mark the presence of significant liver fibrosis (F ≥ 2) in patients with chronic alcohol abuse, chronic viral infection (HBV/HCV), and non-alcoholic fatty liver disease (NAFLD). Results: miRNA-profiling identified miRNA-451a, miRNA-142-5p, Let-7f-5p, and miRNA-378a-3p to be significantly dysregulated upon in vitro HSC activation, and to be highly enriched in their extracellular vesicles, suggesting their potential use as biomarkers. Analysis of the plasma of patients with significant liver fibrosis (F ≥ 2) and no or mild fibrosis (F = 0-1), using miRNA-122-5p and miRNA-29a-3p as positive control, found miRNA-451a, miRNA-142-5p, and Let-7f-5p, but not miRNA-378a-3p, able to distinguish between the two patient populations. Using logistic regression analysis, combining all five dysregulated circulating miRNAs, we created the miRFIB-score with a predictive value superior to the clinical scores Fibrosis-4 (Fib-4), aspartate aminotransferase/alanine aminotransferase (AST/ALT) ratio, and AST to platelet ratio index (APRI). The combination of the miRFIB-score with circulating PDGFRβ-levels further increased the predictive capacity for the diagnosis of significant liver fibrosis. Conclusions: The miRFIB- and miRFIBp-scores are accurate tools for the diagnosis of significant liver fibrosis in a heterogeneous patient population.

scholarly journals Gut Microbiome Contributes to Liver Fibrosis Impact on T Cell Receptor Immune Repertoire

2020 ◽  
Vol 11 ◽  
Author(s):  
Qing Liang ◽  
Meina Zhang ◽  
Yudi Hu ◽  
Wei Zhang ◽  
Ping Zhu ◽  
...  
Keyword(s):  
T Cell ◽  
Liver Fibrosis ◽  
T Cell Receptor ◽  
Stellate Cell ◽  
Cell Receptor ◽  
Rrna Gene ◽  
Immune Microenvironment ◽  
Immune Repertoire ◽  
Liver Fibrogenesis ◽  
The Impact

Gut microbiota (GM) modifies the intrahepatic immune microenvironment, but the underlying mechanisms remain poorly understood. Liver fibrosis-associated imprinting is predicted to be reflected in GM. This study investigated the link between GM and the intrahepatic T cell receptor (TCR) immune repertoire (IR), and whether GM modulates the intrahepatic immune microenvironment via TCR IR during liver fibrosis. We analyzed the correlation between GM and TCR IR during liver fibrogenesis. Accordingly, 16S rRNA gene sequencing (16S-seq) and bulk immune repertoire sequencing (IR-seq) were performed to characterize GM and intrahepatic TCR IR. Fecal microbial transplant (FMT) and TCRβ knockout (TcrbKO) mouse models were employed to determine the biological link between GM and TCR IR in liver fibrosis. We found that GM and intrahepatic TCR IR are highly correlated, with both showing reduced diversity and centralized distribution during liver fibrosis. The restoration of normal intestinal microbiota may reshape intrahepatic TCR IR and delay liver fibrosis. Interestingly, TCR IR ablation abrogated the impact of GM on liver fibrogenesis. Furthermore, GM modulated hepatic stellate cell (HSC) activation via TCR IR-mediated intrahepatic immune milieu. Our study demonstrates that GM, which exhibits cross-talk with the intrahepatic TCR IR, influences the intrahepatic immune microenvironment and liver fibrosis progression.

scholarly journals MXD3 Promotes Obesity and the Androgen Receptor Signaling Pathway in Gender-Disparity Hepatocarcinogenesis

Cells ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 3434
Author(s):  
Yi-Wen Tsai ◽  
Kuo-Shyang Jeng ◽  
Mu-Kuang He ◽  
Yang-Wen Hsieh ◽  
Hsin-Hung Lai ◽  
...  
Keyword(s):  
Young Adults ◽  
Liver Fibrosis ◽  
Molecular Mechanisms ◽  
Metabolic Diseases ◽  
Liver Steatosis ◽  
Gender Disparity ◽  
Transgenic Zebrafish ◽  
Alcoholic Fatty Liver ◽  
Visceral Fat Accumulation ◽  
The Impact

Obesity is closely linked to metabolic diseases, particularly non-alcoholic steatohepatitis (NASH) or non-alcoholic fatty liver disease (NAFLD), ultimately leading to hepatocellular carcinoma (HCC). However, the molecular mechanisms of NASH-associated HCC (NAHCC) remain elusive. To explore the impact of Max dimerization protein 3 (MXD3), a transcription factor that regulates several cellular functions in disorders associated with metabolic diseases, we conditionally expressed Mxd3 proteins using Tet-on mxd3 transgenic zebrafish (MXs) with doxycycline (MXs + Dox) or without doxycycline (MXs − Dox) treatment. Overexpression of global MXD3 (gMX) or hepatic Mxd3 (hMX) was associated with obesity-related NAFLD pathophysiology in gMX + Dox, and liver fibrosis and HCC in hMX + Dox. Oil Red O (ORO)-stained signals were seen in intravascular blood vessels and liver buds of larval gMX + Dox, indicating that Mxd3 functionally promotes lipogenesis. The gMX + Dox-treated young adults exhibited an increase in body weight and visceral fat accumulation. The hMX + Dox-treated young adults showed normal body characteristics but exhibited liver steatosis and NASH-like phenotypes. Subsequently, steatohepatitis, liver fibrosis, and NAHCC were found in 6-month-old gMX + Dox adults compared with gMX − Dox adults at the same stage. Overexpression of Mxd3 also enhanced AR expression accompanied by the increase of AR-signaling pathways resulting in hepatocarcinogenesis in males. Our results demonstrate that global actions of Mxd3 are central to the initiation of obesity in the gMX zebrafish through their effects on adipogenesis and that MXD3 could serve as a therapeutic target for obesity-associated liver diseases.

scholarly journals Non-alcoholic fatty liver disease as a medical and social problem

2021 ◽  
Vol 3 (2) ◽  
pp. 71-80
Author(s):  
Margarita E. Semendyaeva
Keyword(s):  
Metabolic Syndrome ◽  
Liver Disease ◽  
Liver Fibrosis ◽  
Fatty Liver ◽  
Social Problem ◽  
Fatty Liver Disease ◽  
Diagnosis And Treatment ◽  
Alcoholic Fatty Liver ◽  
Alcoholic Steatohepatitis ◽  
Alcoholic Fatty Liver Disease

The article considers the non-alcoholic fatty liver disease as an important medical and social problem. This problem include such questions as metabolic syndrome, essential lipoproteinemia, insulinoresistance. It is possible to consider non-alcoholic steatohepatitis as predictor of liver fibrosis and chirrosis. The questions of diagnosis and treatment are discussed.

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