scholarly journals HFD and HFD-provoked hepatic hypoxia act as reciprocal causation for NAFLD via HIF-independent signaling

2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Xiaofang Zhang ◽  
Caoxin Huang ◽  
Xuejun Li ◽  
Zhaoshui Shangguan ◽  
Wenjing Wei ◽  
...  
Keyword(s):  
Hypoxic Condition ◽  
Mice Model ◽  
Primary Hepatocytes ◽  
Reciprocal Causation ◽  
Alcoholic Fatty Liver ◽  
Metabolic Genes ◽  
Obstructive Sleep ◽  
Oxygen Supplement ◽  
Polymerase Chain ◽  
Hypoxic Treatment

Abstract Background The occurrence of non-alcoholic fatty liver disease (NAFLD) is found to be higher in patients with obstructive sleep apnea (OSA), which is characterized by intermittent hypoxia. Activation of hypoxia-inducible factors has been shown in the development and progression of NAFLD, implying a cause and effects relationship between NAFLD and hypoxia. The present study was designed to investigate the interaction of lipotoxicity and hypoxia in the pathogenesis of NAFLD using mice model with high-fat diet (HFD) feeding or hypoxic treatment. Methods NAFLD model was induced in mice by HFD feeding, and in cultured primary hepatocytes by administration of palmitate acid. Mouse hypoxic model was produced by placing the mice in a Animal incubator with oxygen concentration at 75% followed by a 21% oxygen supplement. Hypoxic condition was mimicked by treating the hepatocytes with cobalt chloride (CoCl2) or 1% oxygen supply. Pimonidazole assay was conducted to evaluate hypoxia. Lipid metabolic genes were measured by real-time polymerase-chain reaction. HIF-1α and HIF-2α genes were silenced by siRNA. Results HFD feeding and palmitate acid treatment provoked severe hepatic hypoxia along with TG accumulation in mice and in cultured primary hepatocytes respectively. Conversely, hypoxia induced hepatic TG accumulation in mice and in cultured primary hepatocytes. Hypoxic treatment inhibited the expression of lipolytic genes, while increased the expression of lipogenicgenes in mice. Although both lipotoxicity and hypoxia could activate hepatic hypoxia-induced factor 1α and 2α, while neither lipotoxicity- nor hypoxia- induced hepatic steatosis was affected when HIF was knocked down. Conclusions HFD resulted in hepatic TG accumulation and concomitant hypoxia. Conversely, hypoxia induced hepatic TG accumulation in mice and in cultured heptocytes. Thus lipotoxicity and hypoxia might work as reciprocal causation and orchestrate to promote the development of NAFLD.

What Non-Alcoholic Fatty Liver Disease Has Got to Do with Obstructive Sleep Apnoea Syndrome and viceversa?

2014 ◽  
Vol 23 (3) ◽  
pp. 291-299 ◽  
Author(s):  
Giovanni Tarantino ◽  
Vincenzo Citro ◽  
Carmine Finelli
Keyword(s):  
Liver Disease ◽  
Fatty Liver ◽  
Obstructive Sleep Apnoea ◽  
Fatty Liver Disease ◽  
Sleep Apnoea ◽  
Obstructive Sleep Apnoea Syndrome ◽  
Alcoholic Fatty Liver ◽  
Sleep Apnoea Syndrome ◽  
Obstructive Sleep ◽  
Alcoholic Fatty Liver Disease

Non-alcoholic fatty liver disease (NAFLD) and obstructive sleep apnoea syndrome (OSAS) are common conditions, frequently encountered in patients with obesity and/or metabolic syndrome. NAFLD and OSAS are complex diseases that involve an interaction of several intertwined factors. Several lines of evidence lend credence to an immune system derangement in these patients, i.e. the low grade chronic inflammation status, reckoned to be the most important factor in causing and maintaining these two illnesses. Furthermore, it is emphasized the main role of spleen involvement, as a novel mechanism. In this review the contribution of the visceral adiposity in both NAFLD and OSAS is stressed as well as the role of intermittent hypoxia. Finally, a post on the prevention of systemic inflammation is made.Abbreviations: ALT: alanine aminotransferase; BMI: body mass index; CCR2: chemokine (C-C motif) receptor 2; CRP: C-reactive protein; CPAP: continuous positive airway pressure; FFA: free fatty acid; IGF-I: insulin-like growth factor; IR: insulin resistance; IL-6: interleukin-6; IH: intermittent hypoxia; IKK-β: IκB kinase β; LPS: lipopolysaccharide; MCP-1: monocyte chemoattractant protein-1; NAFLD: non-alcoholic fatty liver disease; NASH: nonalcoholic steatohepatitis; NEFA: non-esterified fatty acid; NF-κB: nuclear factor-κB; OSAS: obstructive sleep apnoea syndrome; PAI-1: plasminogen activator inhibitor-1; ROS: reactive oxygen species; TNF-α: tumor necrosis factor-α; T2D: type 2 diabetes.

Therapeutic effect of Prdx1 on NAFLD mice may be related to the activation of Nrf-2/HO-1 pathway

2020 ◽  
Vol 26 ◽  
Author(s):  
Ru-Xue Bai ◽  
Ying-Ying Xu ◽  
Yan-Ming Chen ◽  
Geng Qin ◽  
Hui-Fen Wang ◽  
...  
Keyword(s):  
Positive Staining ◽  
Wild Type ◽  
Mice Model ◽  
Alcoholic Fatty Liver ◽  
Liver Histopathology ◽  
Final Weight ◽  
Oil Red O Staining ◽  
Alcoholic Fatty Liver Disease ◽  
Oil Red O ◽  
Liver Tissues

Objective: To investigate the effect of peroxiredoxin1 (Prdx1) on the methionine-choline deficient (MCD)- induced mice model of non-alcoholic fatty liver disease (NAFLD). Methods: Wild type (WT), transgenic Prdx1 over-expressing (TG) and Prdx1 knockout (KO) mice were fed with MCD diet to construct NAFLD model. General parameters was determined followed by detection with HE staining, oil red O staining, Immunofluorescence, Immunohistochemistry, qRT-PCR and Western blotting. The activities of MDA, GPX and SOD were also quantified. Results: Compared with WT + MCD group, mice in KO + MCD group showed the decresed final weight, food intake and the levels of glucose, insulin, total cholesterol and triglyceride, accompanying with the increased FFA, ALT and AST, as well as the aggravated liver histopathology, which was alleviated in TG + MCD group. Also, mice from KO + MCD group had increased F4/80 and CD68 positive staining with the upregulation of pro-inflammatory and fibrogenic factors in liver tissues than those from WT + MCD group, as well as the enhanced MDA and the reduced GPX and SOD, while TG + MCD group demonstrated improvements than the WT + MCD group. Nrf-2/HO-1 pathway in liver tissues from NFALD mice was inhibited, and Prdx1-/- can further reduce the expression of Nrf-2 and HO-1, while Prdx1 overexpression increased Nrf-2 and HO-1 expression. Conclusion: Prdx1 improved oxidative stress, inflammation and fibrosis in liver of NAFLD mice, which may be associate with the activation of Nrf-2/HO-1 pathway.

scholarly journals Sex-dependent dynamics of metabolism in primary mouse hepatocytes

2021 ◽  
Author(s):  
Luise Hochmuth ◽  
Christiane Körner ◽  
Fritzi Ott ◽  
Daniela Volke ◽  
Kaja Blagotinšek Cokan ◽  
...  
Keyword(s):  
Gene Expression ◽  
Amino Acid ◽  
Sexual Dimorphism ◽  
New Drugs ◽  
Model Systems ◽  
Specific Gene ◽  
Primary Hepatocytes ◽  
Alcoholic Fatty Liver ◽  
Male And Female ◽  
Primary Mouse

AbstractThe liver is one of the most sexually dimorphic organs. The hepatic metabolic pathways that are subject to sexual dimorphism include xenobiotic, amino acid and lipid metabolism. Non-alcoholic fatty liver disease and hepatocellular carcinoma are among diseases with sex-dependent prevalence, progression and outcome. Although male and female livers differ in their abilities to metabolize foreign compounds, including drugs, sex-dependent treatment and pharmacological dynamics are rarely applied in all relevant cases. Therefore, it is important to consider hepatic sexual dimorphism when developing new treatment strategies and to understand the underlying mechanisms in model systems. We isolated primary hepatocytes from male and female C57BL6/N mice and examined the sex-dependent transcriptome, proteome and extracellular metabolome parameters in the course of culturing them for 96 h. The sex-specific gene expression of the general xenobiotic pathway altered and the female-specific expression of Cyp2b13 and Cyp2b9 was significantly reduced during culture. Sex-dependent differences of several signaling pathways increased, including genes related to serotonin and melatonin degradation. Furthermore, the ratios of male and female gene expression were inversed for other pathways, such as amino acid degradation, beta-oxidation, androgen signaling and hepatic steatosis. Because the primary hepatocytes were cultivated without the influence of known regulators of sexual dimorphism, these results suggest currently unknown modulatory mechanisms of sexual dimorphism in vitro. The large sex-dependent differences in the regulation and dynamics of drug metabolism observed during cultivation can have an immense influence on the evaluation of pharmacodynamic processes when conducting initial preclinical trials to investigate potential new drugs.

scholarly journals Non-alcoholic fatty liver disease in mice with hepatocyte-specific deletion of mitochondrial fission factor

Diabetologia ◽  
2021 ◽  
Author(s):  
Yukina Takeichi ◽  
Takashi Miyazawa ◽  
Shohei Sakamoto ◽  
Yuki Hanada ◽  
Lixiang Wang ◽  
...  
Keyword(s):  
Er Stress ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fission ◽  
Primary Hepatocytes ◽  
Alcoholic Fatty Liver ◽  
Expression Of Genes ◽  
Specific Deletion

Abstract Aims/hypothesis Mitochondria are highly dynamic organelles continuously undergoing fission and fusion, referred to as mitochondrial dynamics, to adapt to nutritional demands. Evidence suggests that impaired mitochondrial dynamics leads to metabolic abnormalities such as non-alcoholic steatohepatitis (NASH) phenotypes. However, how mitochondrial dynamics are involved in the development of NASH is poorly understood. This study aimed to elucidate the role of mitochondrial fission factor (MFF) in the development of NASH. Methods We created mice with hepatocyte-specific deletion of MFF (MffLiKO). MffLiKO mice fed normal chow diet (NCD) or high-fat diet (HFD) were evaluated for metabolic variables and their livers were examined by histological analysis. To elucidate the mechanism of development of NASH, we examined the expression of genes related to endoplasmic reticulum (ER) stress and lipid metabolism, and the secretion of triacylglycerol (TG) using the liver and primary hepatocytes isolated from MffLiKO and control mice. Results MffLiKO mice showed aberrant mitochondrial morphologies with no obvious NASH phenotypes during NCD, while they developed full-blown NASH phenotypes in response to HFD. Expression of genes related to ER stress was markedly upregulated in the liver from MffLiKO mice. In addition, expression of genes related to hepatic TG secretion was downregulated, with reduced hepatic TG secretion in MffLiKO mice in vivo and in primary cultures of MFF-deficient hepatocytes in vitro. Furthermore, thapsigargin-induced ER stress suppressed TG secretion in primary hepatocytes isolated from control mice. Conclusions/interpretation We demonstrated that ablation of MFF in liver provoked ER stress and reduced hepatic TG secretion in vivo and in vitro. Moreover, MffLiKO mice were more susceptible to HFD-induced NASH phenotype than control mice, partly because of ER stress-induced apoptosis of hepatocytes and suppression of TG secretion from hepatocytes. This study provides evidence for the role of mitochondrial fission in the development of NASH. Graphical abstract

scholarly journals 343 Obstructive Sleep Apnea and Hypoxia are Associated With More Advanced Fibrosis in Pediatric Non-Alcoholic Fatty Liver Disease

2012 ◽  
Vol 142 (5) ◽  
pp. S-80 ◽  
Author(s):  
Shikha S. Sundaram ◽  
Jillian S. Sullivan ◽  
Ronald J. Sokol ◽  
Kristen N. Robbins ◽  
Kelley Capocelli ◽  
...  
Keyword(s):  
Obstructive Sleep Apnea ◽  
Liver Disease ◽  
Sleep Apnea ◽  
Fatty Liver ◽  
Fatty Liver Disease ◽  
Advanced Fibrosis ◽  
Alcoholic Fatty Liver ◽  
Obstructive Sleep ◽  
Alcoholic Fatty Liver Disease

GCSF deficiency attenuates non-alcoholic fatty liver disease through regulating GCSFR-SOCS3-JAK-STAT3 pathway and immune cells infiltration

2021 ◽  
Author(s):  
Yuwei Zhang ◽  
Xuefeng Zhou ◽  
Peihao Liu ◽  
Xueyang Chen ◽  
Jie Zhang ◽  
...  
Keyword(s):  
Liver Disease ◽  
Fatty Liver ◽  
Immune Cells ◽  
Fatty Liver Disease ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Primary Hepatocytes ◽  
Alcoholic Fatty Liver ◽  
Stimulating Factor ◽  
Alcoholic Fatty Liver Disease

Granulocyte colony stimulating factor (GCSF) is a cytokine with immunomodulation effects. However, little is known about its role in metabolic diseases. In the current study we aimed to explore the role of GCSF in non-alcoholic fatty liver disease (NAFLD). GCSF-/- mice were used to investigate the function of GCSF in vivo after high fat diet (HFD). Primary hepatocytes were used for evaluating the function of GCSF in vitro. Liver immune cells were isolated and analyzed by flow cytometry. Our results showed that GCSF administration significantly increased serum triglyceride (TG) levels in patients. Circulating GCSF was markedly elevated in HFD-fed mice. GCSF-/- mice exhibited alleviated HFD-induced obesity, insulin resistance and hepatic steatosis. Extra administration of GCSF significantly aggravated palmitic acid (PA)-induced lipid accumulation in primary hepatocytes. Mechanically, GCSF could bind to granulocyte colony stimulating factor receptor (GCSFR) and regulate suppressors of cytokine signaling 3, Janus kinase, signal transducer and activator of transcription 3 (SOCS3-JAK-STAT3) pathway. GCSF also enhanced hepatic neutrophils and macrophages infiltration, thereby modulating NAFLD. These findings suggest that GCSF plays an important regulatory role in NAFLD and may be a potential therapeutic target for NAFLD.

scholarly journals XBP1 links the 12-hour clock to NAFLD and regulation of membrane fluidity and lipid homeostasis

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Huan Meng ◽  
Naomi M. Gonzales ◽  
David M. Lonard ◽  
Nagireddy Putluri ◽  
Bokai Zhu ◽  
...  
Keyword(s):  
Circadian Clock ◽  
Membrane Fluidity ◽  
Phospholipid Composition ◽  
Cellular Membrane ◽  
Lipid Homeostasis ◽  
Alcoholic Fatty Liver ◽  
The Core ◽  
Metabolic Genes ◽  
Rate Limiting ◽  
Alcoholic Fatty Liver Disease

AbstractA distinct 12-hour clock exists in addition to the 24-hour circadian clock to coordinate metabolic and stress rhythms. Here, we show that liver-specific ablation of X-box binding protein 1 (XBP1) disrupts the hepatic 12-hour clock and promotes spontaneous non-alcoholic fatty liver disease (NAFLD). We show that hepatic XBP1 predominantly regulates the 12-hour rhythmicity of gene transcription in the mouse liver and demonstrate that perturbation of the 12-hour clock, but not the core circadian clock, is associated with the onset and progression of this NAFLD phenotype. Mechanistically, we provide evidence that the spliced form of XBP1 (XBP1s) binds to the hepatic 12-hour cistrome to directly regulate the 12-hour clock, with a periodicity paralleling the harmonic activation of the 12-hour oscillatory transcription of many rate-limiting metabolic genes known to have perturbations in human metabolic disease. Functionally, we show that Xbp1 ablation significantly reduces cellular membrane fluidity and impairs lipid homeostasis via rate-limiting metabolic processes in fatty acid monounsaturated and phospholipid remodeling pathways. These findings reveal that genetic disruption of the hepatic 12-hour clock links to the onset and progression of NAFLD development via transcriptional regulator XBP1, and demonstrate a role for XBP1 and the 12-hour clock in the modulation of phospholipid composition and the maintenance of lipid homeostasis.

scholarly journals Antrodan Alleviates High-Fat and High-Fructose Diet-Induced Fatty Liver Disease in C57BL/6 Mice Model via AMPK/Sirt1/SREBP-1c/PPARγ Pathway

2020 ◽  
Vol 21 (1) ◽  
pp. 360 ◽  
Author(s):  
Charng-Cherng Chyau ◽  
Hsueh-Fang Wang ◽  
Wen-Juan Zhang ◽  
Chin-Chu Chen ◽  
Shiau-Huei Huang ◽  
...  
Keyword(s):  
Liver Disease ◽  
Fatty Liver ◽  
Fatty Liver Disease ◽  
Mice Model ◽  
High Fat ◽  
Alcoholic Fatty Liver ◽  
High Fructose Diet ◽  
High Fructose ◽  
Ant Control ◽  
Alcoholic Fatty Liver Disease

Non-alcoholic fatty liver disease (NAFLD) and -steatohepatitis (NASH) imply a state of excessive fat built-up in livers with/or without inflammation and have led to serious medical concerns in recent years. Antrodan (Ant), a purified β-glucan from A. cinnamomea has been shown to exhibit tremendous bioactivity, including hepatoprotective, antihyperlipidemic, antiliver cancer, and anti-inflammatory effects. Considering the already well-known alleviating bioactivity of A. cinnamomea for the alcoholic steatohepatitis (ASH), we propose that Ant can be beneficial to NAFLD, and that the AMPK/Sirt1/PPARγ/SREBP-1c pathways may be involved in such alleviations. To uncover this, we carried out this study with 60 male C57BL/6 mice fed high-fat high-fructose diet (HFD) for 60 days, in order to induce NAFLD/NASH. Mice were then grouped and treated (by oral administration) as: G1: control; G2: HFD (HFD control); G3: Ant, 40 mgkg (Ant control); G4: HFD+Orlistat (10 mg/kg) (as Orlistat control); G5: HFD+Ant L (20 mg/kg); and G6: HFD+Ant H (40 mg/kg) for 45 days. The results indicated Ant at 40 mg/kg effectively suppressed the plasma levels of malondialdehyde, total cholesterol, triglycerides, GOT, GPT, uric acid, glucose, and insulin; upregulated leptin, adiponectin, pAMPK, Sirt1, and down-regulated PPARγ and SREBP-1c. Conclusively, Ant effectively alleviates NAFLD via AMPK/Sirt1/CREBP-1c/PPARγ pathway.

scholarly journals Complications of Non-Alcoholic Fatty Liver Disease in Extrahepatic Organs

Diagnostics ◽  
2020 ◽  
Vol 10 (11) ◽  
pp. 912
Author(s):  
Wataru Tomeno ◽  
Kento Imajo ◽  
Takuya Takayanagi ◽  
Yu Ebisawa ◽  
Kosuke Seita ◽  
...  
Keyword(s):  
Liver Disease ◽  
Fatty Liver ◽  
Cause Of Death ◽  
Fatty Liver Disease ◽  
Sleep Apnea Syndrome ◽  
Screening Method ◽  
Alcoholic Fatty Liver ◽  
Obstructive Sleep ◽  
Alcoholic Fatty Liver Disease ◽  
Related Mortality

Non-alcoholic fatty liver disease (NAFLD) is now recognized as the most common chronic liver disease worldwide, along with the concurrent epidemics of metabolic syndrome and obesity. Patients with NAFLD have increased risks of end-stage liver disease, hepatocellular carcinoma, and liver-related mortality. However, the largest cause of death among patients with NAFLD is cardiovascular disease followed by extrahepatic malignancies, whereas liver-related mortality is only the third cause of death. Extrahepatic complications of NAFLD include chronic kidney disease, extrahepatic malignancies (such as colorectal cancer), psychological dysfunction, gastroesophageal reflux disease, obstructive sleep apnea syndrome, periodontitis, hypothyroidism, growth hormone deficiency, and polycystic ovarian syndrome. The objective of this narrative review was to summarize recent evidences about extrahepatic complications of NAFLD, with focus on the prevalent/incident risk of such diseases in patients with NAFLD. To date, an appropriate screening method for extrahepatic complications has not yet been determined. Collaborative care with respective experts seems to be necessary for patient management because extrahepatic complications can occur across multiple organs. Further studies are needed to reveal risk profiles at baseline and to determine an appropriate screening method for extrahepatic diseases.

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