scholarly journals Increase of E3 ubiquitin ligase NEDD4 expression leads to degradation of its target proteins PTEN/IGF1R during the formation of goose fatty liver

2020 ◽  
Vol 98 (9) ◽  
Author(s):  
Chunchi Yan ◽  
Minmeng Zhao ◽  
Shuo Li ◽  
Tongjun Liu ◽  
Cheng Xu ◽  
...  
Keyword(s):  
Fatty Liver ◽  
Mrna Expression ◽  
Messenger Rna ◽  
Quantitative Polymerase Chain Reaction ◽  
Normal Liver ◽  
Protective Mechanism ◽  
Nonalcoholic Fatty Liver ◽  
Target Proteins ◽  
Protein Levels ◽  
Gene 4

Abstract Goose fatty liver may have a unique protective mechanism as it does not show a pathological injury even in the case of severe steatosis. Although neural precursor cell-expressed developmentally downregulated gene 4 (NEDD4) participates in repair and regeneration of injured liver through its target proteins, its role in nonalcoholic fatty liver disease remains unknown. Using quantitative polymerase chain reaction (PCR) and immunoblot analyses, here, we found that the messenger RNA (mRNA) and protein expressions of NEDD4 were induced in goose fatty liver compared with normal liver. The mRNA expression of the gene of phosphate and tension homology deleted on chromosome ten (PTEN) and insulin-like growth factor 1 receptor (IGF1R) was also induced in goose fatty liver; however, their protein expression was or tended to be suppressed. Moreover, the co-immunoprecipitation analysis indicated that there was a physical association between NEDD4 and PTEN in goose liver, which was consistent with the ubiquitination of PTEN in goose fatty liver. Furthermore, NEDD4 overexpression in goose primary hepatocytes suppressed the PTEN and IGF1R protein levels without a significant effect on their mRNA expression. In conclusion, the increased expression of NEDD4 leads to the degradation of PTEN and IGF1R proteins through ubiquitination in goose fatty liver, suggesting that NEDD4 may protect goose fatty liver from severe steatosis-associated injury via its target proteins during the development of goose fatty liver.

scholarly journals Olanzapine leads to nonalcoholic fatty liver disease through the apolipoprotein A5 pathway

2021 ◽  
Author(s):  
Rong Li ◽  
Wenqiang Zhu ◽  
Piaopiao Huang ◽  
Yang Yang ◽  
Fei Luo ◽  
...  
Keyword(s):  
Liver Disease ◽  
Fatty Liver ◽  
Mrna Expression ◽  
Hepg2 Cells ◽  
Fatty Liver Disease ◽  
Nonalcoholic Fatty Liver ◽  
Apolipoprotein A5 ◽  
Protein Levels ◽  
Hepatocyte Steatosis

ABSTRACTThe antipsychotic drug olanzapine was reported to induce nonalcoholic fatty liver disease (NAFLD), whereas the underlying mechanism remains incompletely understood. This study investigated whether apolipoprotein A5 (apoA5) and sortilin, two interactive factors involved in NAFLD pathogenesis, are implicated in olanzapine-induced NAFLD. In the present study, at week 8, olanzapine treatment successfully induced hepatic steatosis in male C57 BL/6J mice, even when fed a normal chow diet, which was independent of animal body weight gain. Likewise, olanzapine effectively mediated hepatocyte steatosis in human HepG2 cells in vitro, characterized by substantially elevated intracellular lipid droplets. Increased plasma triglyceride concentration and decreased plasma apoA5 levels were observed in mice treated for 8 weeks with olanzapine. Surprisingly, olanzapine markedly enhanced hepatic apoA5 protein levels in mice, without a significant effect on rodent hepatic ApoA5 mRNA expression. Our in vitro study showed that olanzapine reduced apoA5 protein levels in the medium and enhanced apoA5 protein expression in hepatocytes, whereas this drug exerted no effect on hepatocyte APOA5 mRNA expression. By transfecting APOA5 siRNA into HepG2 cells, it was demonstrated that APOA5 knockdown effectively reversed olanzapine-induced hepatocyte steatosis. In addition, olanzapine drastically increased sortilin mRNA and protein levels in vivo and in vitro. Interestingly, SORT1 knockdown reduced intracellular apoA5 protein expression and increased medium apoA5 protein levels in vitro, without affecting intracellular APOA5 mRNA expression. Furthermore, SORT1 knockdown greatly ameliorated hepatocyte steatosis in vitro. This study provides the first evidence that sortilin inhibits the hepatic apoA5 secretion that is attributable to olanzapine-induced NAFLD, which provides new insight into effective strategies against NAFLD for patients with schizophrenia administered olanzapine.

scholarly journals Estrogen Metabolism in Abdominal Subcutaneous and Visceral Adipose Tissue in Postmenopausal Women

2017 ◽  
Vol 102 (12) ◽  
pp. 4588-4595 ◽  
Author(s):  
Natalia Hetemäki ◽  
Hanna Savolainen-Peltonen ◽  
Matti J Tikkanen ◽  
Feng Wang ◽  
Hanna Paatela ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Mrna Expression ◽  
Postmenopausal Women ◽  
Messenger Rna ◽  
Metabolic Diseases ◽  
Quantitative Polymerase Chain Reaction ◽  
Subcutaneous Fat ◽  
Estrogen Metabolism ◽  
Serum Samples ◽  
Estrogen Exposure

Abstract Context In postmenopausal women, adipose tissue (AT) levels of estrogens exceed circulating concentrations. Although increased visceral AT after menopause is related to metabolic diseases, little is known about differences in estrogen metabolism between different AT depots. Objective We compared concentrations of and metabolic pathways producing estrone and estradiol in abdominal subcutaneous and visceral AT in postmenopausal women. Design, Setting, Patients, and Interventions AT and serum samples were obtained from 37 postmenopausal women undergoing surgery for nonmalignant gynecological reasons. Serum and AT estrone, estradiol, and serum estrone sulfate (E1S) concentrations were quantitated using liquid chromatography-tandem mass spectrometry. Activity of steroid sulfatase and reductive 17β-hydroxysteroid dehydrogenase enzymes was measured using radiolabeled precursors. Messenger RNA (mRNA) expression of estrogen-converting enzymes was analyzed by real-time reverse transcription quantitative polymerase chain reaction. Results Estrone concentration was higher in visceral than subcutaneous AT (median, 928 vs 706 pmol/kg; P = 0.002) and correlated positively with body mass index (r = 0.46; P = 0.011). Both AT depots hydrolyzed E1S to estrone, and visceral AT estrone and estradiol concentrations correlated positively with serum E1S. Compared with visceral AT, subcutaneous AT produced more estradiol from estrone (median rate of estradiol production, 1.02 vs 0.57 nmol/kg AT/h; P = 0.004). In visceral AT, the conversion of estrone to estradiol increased with waist circumference (r = 0.65; P = 0.022), and estradiol concentration correlated positively with mRNA expression of HSD17B7 (r = 0.76; P = 0.005). Conclusions Both estrone and estradiol production in visceral AT increased with adiposity, but estradiol was produced more effectively in subcutaneous fat. Both AT depots produced estrone from E1S. Increasing visceral adiposity could increase overall estrogen exposure in postmenopausal women.

Lower antioxidant capacity in the prefrontal cortex of individuals with schizophrenia

2017 ◽  
Vol 52 (7) ◽  
pp. 690-698 ◽  
Author(s):  
Yiru Zhang ◽  
Vibeke Sørensen Catts ◽  
Cynthia Shannon Weickert
Keyword(s):  
Prefrontal Cortex ◽  
Antioxidant Capacity ◽  
Mrna Expression ◽  
Antioxidant System ◽  
Messenger Rna ◽  
Total Glutathione ◽  
Protein Levels ◽  
Significant Difference ◽  
Dorsolateral Prefrontal ◽  
And Control

Objective: The glutathione (GSH) pathway is the main antioxidant system to protect against oxidative stress in the human brain. In this study, we tested whether molecular components of the GSH antioxidant system are changed in dorsolateral prefrontal cortex tissue from people with schizophrenia compared to controls. Method: The levels of total glutathione and reduced GSH were determined by fluorometric assay via quantifying thiols in extracts from frontal cortex of 68 people. Immunoblotting was used to measure levels of enzymes responsible for maintaining GSH, the glutamyl-cysteine ligase (GCL) catalytic subunit (GCLC) and the GSH peroxidase (GPx)-like protein ( n = 74). Quantitative reverse transcription polymerase chain reaction (RT-PCR) was used to measure GCLC messenger RNA (mRNA) expression. Results: Both total glutathione ( t(66) = 2.467, p = 0.016) and reduced GSH ( t(66) = 3.001, p = 0.004) levels were significantly less in people with schizophrenia than in controls. However, there were no significant differences in either GCLC-like protein ( t(72) = −1.077, p = 0.285) or GCLC mRNA expression ( t(71) = −0.376, p = 0.708) between people with schizophrenia and control subjects. There was also no significant difference of GPx-like protein levels between schizophrenia and controls ( t(72) = −0.060, p = 0.952). Moreover, no significant correlations of putative confounding factors with GSH changes were detected. Discussion: These results suggest that people with schizophrenia have impaired GSH antioxidant capacity, alongside normal levels of key regulatory proteins.

Environmentally Relevant Level of Aflatoxin B1 Dysregulates Human Dendritic Cells Through Signaling on Key Toll-Like Receptors

2014 ◽  
Vol 33 (3) ◽  
pp. 175-186 ◽  
Author(s):  
Azam Mohammadi ◽  
Jalil Mehrzad ◽  
Mahmoud Mahmoudi ◽  
Marion Schneider
Keyword(s):  
Dendritic Cells ◽  
Messenger Rna ◽  
Molecular Mechanisms ◽  
Quantitative Polymerase Chain Reaction ◽  
Immune Surveillance ◽  
Toll Like Receptors ◽  
Myeloid Dendritic Cells ◽  
Protein Levels ◽  
Tlr4 Mrna ◽  
Relevant Level

Aflatoxins (AFs) are highly hazardous fungal biometabolites usually present in feeds and foods. Aflatoxin B1 (AFB1) is the most toxic and a known carcinogen. Toll-like receptors (TLRs), highly expressed by myeloid dendritic cells (DC), are key innate immune-surveillance molecules. Toll-like receptors not only sense pathogen-associated molecular patterns but also contribute to infections and cancer. To assess AFB1–TLR interactions on human myeloid DC, pure CD11c+ DC were generated from monocytes isolated from healthy individuals and then exposed to relevant level of AFB1 for 2 hours. Both quantitative polymerase chain reaction and flow cytometric assays were used to quantify, respectively, expression of TLR2 and TLR4 at the messenger RNA (mRNA) and protein levels in these DC. Levels of interleukin (IL) 1β, IL-6, and IL-10 were also analyzed in AFB1- and mock-treated DC. Compared to nontreated CD11c+ DC, expression levels of both TLR2 and TLR4 mRNA and proteins were significantly upregulated in AFB1-treated cells. Further, although IL-10 levels in AFB1-treated DC were similar to those in the mock-treated DC, the AFB1-exposed DC secreted higher amounts of IL-1β and IL-6. Dendritic cells are sensitive to environmentally relevant level of AFB1, and TLR2 and TLR4 are involved in sensing AFB1. Considering the broad roles of TLR2, TLR4, and DC in immunity and infections, our novel findings open a new door to understanding the molecular mechanisms and functional consequences of AFB1 in inducing immunodysregulation, immunotoxicity, and thus (non)infectious diseases in humans.

scholarly journals Endocannabinoid Receptors Gene Expression in Morbidly Obese Women with Nonalcoholic Fatty Liver Disease

2014 ◽  
Vol 2014 ◽  
pp. 1-7 ◽  
Author(s):  
Teresa Auguet ◽  
Alba Berlanga ◽  
Esther Guiu-Jurado ◽  
Ximena Terra ◽  
Salomé Martinez ◽  
...  
Keyword(s):  
Liver Disease ◽  
Fatty Liver ◽  
Mrna Expression ◽  
Nonalcoholic Fatty Liver Disease ◽  
Fatty Liver Disease ◽  
Enzyme Linked Immunosorbent Assay ◽  
Morbidly Obese ◽  
Receptor Subtypes ◽  
Obese Women ◽  
Nonalcoholic Fatty Liver

Background. Recent reports suggest a role for the endocannabinoid system in the pathology of nonalcoholic fatty liver disease (NAFLD). The aim of this study was to investigate the relationship between liver expression of cannabinoid (CB) receptor subtypes, CB1 and CB2, in morbidly obese (MO) women with different histological stages of NAFLD.Methods. We analysed hepatic CB1 and CB2 mRNA expression, and the expression of genes involved in lipid metabolism in 72 MO women, subclassified by liver histology into MO with normal liver (NL,n=16), simple steatosis (SS,n=28), and nonalcoholic steatohepatitis (NASH,n=28) by enzyme-linked immunosorbent assay and RT-PCR.Results. We found that CB1 mRNA expression was significantly higher in NASH compared with SS and correlated negatively with PPARα. Regarding CB2, CB2 mRNA expression correlated positively with ACC1, PPARγ, IL6, TNFα, resistin, and adiponectin.Conclusions. The increased expression of CB1 in NASH and the negative correlation with PPARαsuggest a deleterious role of CB1 in NAFLD. Regarding CB2, its positive correlation with the anti-inflammatory molecule adiponectin and, paradoxically, with inflammatory genes suggests that this receptor has a dual role. Taken together, our results suggest that endocannabinoid receptors might be involved in the pathogenesis of NAFLD, a finding which justifies further study.

Low Levels of Serum β-Carotene and β-Carotene/Retinol Ratio Are Associated with Histological Severity in Nonalcoholic Fatty Liver Disease Patients

2019 ◽  
Vol 74 (2) ◽  
pp. 156-164 ◽  
Author(s):  
Lijun Wang ◽  
Chenghe Ding ◽  
Fangfang Zeng ◽  
Huilian Zhu
Keyword(s):  
Liver Disease ◽  
Fatty Liver ◽  
Nonalcoholic Fatty Liver Disease ◽  
Fatty Liver Disease ◽  
Normal Liver ◽  
Hplc Method ◽  
Nonalcoholic Fatty Liver ◽  
Face To Face ◽  
Β Carotene

β-Carotene has been reported to alleviate hepatic steatosis (SS), inflammation, and fibrosis in vivo and vitro studies. However, the clinical relevance of serum β-carotene and β-carotene-to-retinol (SC/SR) ratio with histological severity in nonalcoholic fatty liver disease (NAFLD) patients is unknown. This case-control study enrolled 24 control subjects and 62 NAFLD patients. Liver biopsies were collected and histological characteristics were assessed. Information with regard to demographic, anthropometric and dietary intake was assessed by face-to-face interviews with questionnaire. Serum β-carotene and retinol concentrations were determined by the HPLC method. Serum β-carotene and SC/SR levels in NAFLD patients were significantly lower than these in controls (0.23 ± 0.01 vs. 0.35 ± 0.04 μmol/L, 0.38 ± 0.03 vs. 0.84 ± 0.10). Compared with individuals without SS, both β-carotene and SC/SR levels were significantly decreased in those with moderate SS (0.34 ± 0.03 vs. 0.21 ± 0.02 μmol/L, 0.76 ± 0.09 vs. 0.37 ± 0.05). Subjects with mild inflammation had a significantly lower β-carotene and SC/SR levels than those without inflammation (0.23 ± 0.01 vs. 0.33 ± 0.04 μmol/L, 0.77 ± 0.09 vs. 0.38 ± 0.03). Serum SC/SR was significantly lower in patients with mild fibrosis than those without fibrosis (0.45 [0.27–0.83] vs. 0.34 [0.26–0.51]). According to the NAFLD Activity Scoring score, both β-carotene and SC/SR gradually decreased with disease progression from normal liver, simple SS to steatohepatitis borderline (ptrend ≤ 0.001). These results show that NAFLD patients have lower circulating β-carotene concentration and SC/SR ratio, which are associated with the histological severity of NAFLD.

scholarly journals Aspirin Improves Nonalcoholic Fatty Liver Disease and Atherosclerosis through Regulation of the PPARδ-AMPK-PGC-1α Pathway in Dyslipidemic Conditions

2020 ◽  
Vol 2020 ◽  
pp. 1-17 ◽  
Author(s):  
Yoon-Mi Han ◽  
Yong-Jik Lee ◽  
Yoo-Na Jang ◽  
Hyun-Min Kim ◽  
Hong Seog Seo ◽  
...  
Keyword(s):  
Liver Disease ◽  
Oxidative Phosphorylation ◽  
Fatty Liver ◽  
Nonalcoholic Fatty Liver Disease ◽  
Fatty Liver Disease ◽  
Mannose Receptor ◽  
Liver Cells ◽  
Vascular Endothelial ◽  
Nonalcoholic Fatty Liver ◽  
Protein Levels

This study is aimed at elucidating how aspirin could systemically and simultaneously normalize nonalcoholic fatty liver disease (NAFLD) and atherosclerosis through both in vitro and in vivo studies in hyperlipidemic conditions. We evaluated the effects and mechanism of aspirin on the levels of various biomarkers related to NAFLD, atherosclerosis, and oxidative phosphorylation in cells and animals of hyperlipidemic conditions. The protein levels of biomarkers (PPARδ, AMPK, and PGC-1α) involved in oxidative phosphorylation in both the vascular endothelial and liver cells were elevated by the aspirin in hyperlipidemic condition. Also in the stimulation pathway of oxidative phosphorylation by aspirin, PPARδ was a superior regulator than AMPK and PGC-1α in HepG2 cells. In the vascular endothelial cells, the phosphorylated endothelial nitric oxide synthase level was increased by the treatment. The protein levels of biomarkers related to lipid synthesis were decreased by the treatment in the liver cells. In rabbits administered with cholesterol diet, the levels of triglyceride, HDL-cholesterol, and alanine amino transferase in serums were ameliorated by the aspirin treatment, the levels of ATP and TNFα were increased or decreased, respectively, by the aspirin in liver and aorta tissues, and mannose receptor and C-C chemokine receptor type 2 levels were increased or decreased by the aspirin in spleen, respectively. The elevated levels of macrophage antigen, angiotensin II type1 receptor, and lipid accumulation were decreased in both the liver and aorta tissues in the aspirin-treated group. In conclusion, aspirin can systemically and simultaneously ameliorate NAFLD and atherosclerosis by inhibiting lipid biosynthesis and inflammation and by elevating catabolic metabolism through the activation of the PPARδ-AMPK-PGC-1α pathway. Furthermore, aspirin may normalize atherosclerosis and NAFLD by modulating the mannose receptor and CCR2 in macrophages.

scholarly journals Protective role of arnebin-1 in rats with nonalcoholic fatty liver disease

2019 ◽  
Vol 47 (3) ◽  
pp. 1250-1263
Author(s):  
Weijia Yang ◽  
Minchun Yang ◽  
Hui Yao ◽  
Yelin Ma ◽  
Xuanxuan Ren ◽  
...  
Keyword(s):  
Liver Disease ◽  
Liver Fibrosis ◽  
Fatty Liver ◽  
Nonalcoholic Fatty Liver Disease ◽  
Fatty Liver Disease ◽  
Histopathological Examination ◽  
Quantitative Polymerase Chain Reaction ◽  
Tissue Inhibitor Of Metalloproteinase ◽  
Sprague Dawley ◽  
Nonalcoholic Fatty Liver

Objective To examine the effects of arnebin-1 on nonalcoholic fatty liver disease (NAFLD) induced by a high-fat diet (HFD). Methods Male Sprague–Dawley rats were fed an HFD for 10 weeks and then treated with arnebin-1 at a dose of 5, 10 or 20 mg/kg/day by gavage for a further 12 weeks of a 22-week HFD. Peripheral blood and liver tissues were collected for biochemical and histopathological examination. The mechanisms of arnebin-1 on liver fibrosis and insulin resistance (IR) were determined by Western blotting and real-time quantitative polymerase chain reaction. Results Arnebin-1 treatment attenuated the increase of total cholesterol, triglycerides, low-density lipoprotein cholesterol, aspartate aminotransferase and alanine aminotransferase in serum and lipid accumulation in the livers of HFD-fed rats. Furthermore, arnebin-1 abrogated HFD-induced liver fibrosis and the increase of fibrotic biomarkers. The HFD-induced decrease of hepatic proliferator-activated receptor γ and pro-matrix-metalloproteinase (MMP)-9 levels and the increase of tissue inhibitor of metalloproteinase-1 (TIMP-1) levels were reversed after arnebin-1. Arnebin-1 attenuated IR through activating the insulin receptor substrate-1/Akt/mTOR signalling pathway. Conclusion This study demonstrated that arnebin-1 ameliorates NAFLD, in part, by attenuating hepatic fibrosis and IR, suggesting that arnebin-1 may be a therapeutic agent for NAFLD treatment.

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