scholarly journals Obesity and binge alcohol intake are deadly combination to induce steatohepatitis: A model of high-fat diet and binge ethanol intake

2020 ◽  
Vol 26 (4) ◽  
pp. 586-594 ◽  
Author(s):  
Seonghwan Hwang ◽  
Tianyi Ren ◽  
Bin Gao
Keyword(s):  
Liver Injury ◽  
Binge Drinking ◽  
Mouse Models ◽  
High Fat Diet ◽  
Neutrophil Infiltration ◽  
Mitogen Activated Protein Kinase ◽  
High Fat ◽  
Hepatic Expression ◽  
Underlying Mechanisms ◽  
Binge Ethanol

Obesity and binge drinking often coexist and work synergistically to promote steatohepatitis; however, the underlying mechanisms remain obscure. In this mini-review, we briefly summarize clinical evidence of the synergistical effect of obesity and heavy drinking on steatohepatitis and discuss the underlying mechanisms obtained from the study of several mouse models. High-fat diet (HFD) feeding and binge ethanol synergistically induced steatohepatitis and fibrosis in mice with significant intrahepatic neutrophil infiltration; such HFD-plus-ethanol treatment markedly up-regulated the hepatic expression of many chemokines with the highest fold (approximately 30-fold) induction of chemokine (C-X-C motif) ligand 1 (<i>Cxcl1</i>), which contributes to hepatic neutrophil infiltration and liver injury. Furthermore, HFD feeding activated peroxisome proliferator-activated receptor gamma that subsequently inhibited CXCL1 upregulation in hepatocytes, thereby forming a negative feedback loop to prevent neutrophil overaction; whereas binge ethanol blocked this loop and then exacerbated CXCL1 elevation, neutrophil infiltration, and liver injury. Interestingly, inflamed mouse hepatocytes attracted neutrophils less effectively than inflamed human hepatocytes due to the lower induction of CXCL1 and the lack of the interleukin (IL)-8 gene in the mouse genome, which may be one of the reasons for difficulty in development of mouse models of alcoholic steatohepatitis and nonalcoholic steatohepatitis (NASH). Hepatic overexpression of <i>Cxcl1</i> and/or IL-8 promoted steatosis-to-NASH progression in HFD-fed mice by inducing neutrophil infiltration, oxidative stress, hepatocyte death, fibrosis, and p38 mitogen-activated protein kinase activation. Collectively, obesity and binge drinking synergistically promote steatohepatitis via the induction of CXCL1 and subsequent hepatic neutrophil infiltration.

scholarly journals Effects of gut microbiota on leptin expression and body weight are lessened by high-fat diet in mice

2020 ◽  
Vol 124 (4) ◽  
pp. 396-406 ◽  
Author(s):  
Hongyang Yao ◽  
Chaonan Fan ◽  
Xiuqin Fan ◽  
Yuanyuan Lu ◽  
Yuanyuan Wang ◽  
...  
Keyword(s):  
Body Weight ◽  
Gut Microbiota ◽  
High Fat Diet ◽  
Body Weight Gain ◽  
High Fat ◽  
Hepatic Expression ◽  
Reduced Body ◽  
Expression Of Genes ◽  
Underlying Mechanisms ◽  
Leptin Expression

AbstractAberration in leptin expression is one of the most frequent features in the onset and progression of obesity, but the underlying mechanisms are still unclear and need to be clarified. This study investigated the effects of the absence of gut microbiota on body weight and the expression and promoter methylation of the leptin. Male C57 BL/6 J germ-free (GF) and conventional (CV) mice (aged 4–5 weeks) were fed either a normal-fat diet (NFD) or a high-fat diet (HFD) for 16 weeks. Six to eight mice from each group, at 15 weeks, were administered exogenous leptin for 7 d. Leptin expression and body weight gain in GF mice were increased by NFD with more CpG sites hypermethylated at the leptin promoter, whereas there was no change with HFD, compared with CV mice. Adipose or hepatic expression of genes associated with fat synthesis (Acc1, Fas and Srebp-1c), hydrolysis and oxidation (Atgl, Cpt1a, Cpt1c, Ppar-α and Pgc-1α) was lower, and hypothalamus expression of Pomc and Socs3 was higher in GF mice than levels in CV mice, particularly with NFD feeding. Exogenous leptin reduced body weight in both types of mice, with a greater effect on CV mice with NFD. Adipose Lep-R expression was up-regulated, and hepatic Fas and hypothalamic Socs3 were down-regulated in both types of mice. Expression of fat hydrolysis and oxidative genes (Atgl, Hsl, Cpt1a, Cpt1c, Ppar-α and Pgc-1α) was up-regulated in CV mice. Therefore, the effects of gut microbiota on the leptin expression and body weight were affected by dietary fat intake.

Vitamin A status affects weight gain and hepatic glucose metabolism in rats fed a high-fat diet

2019 ◽  
Vol 97 (5) ◽  
pp. 545-553 ◽  
Author(s):  
Heqian Kuang ◽  
Cheng-hsin Wei ◽  
Tiannan Wang ◽  
Jennifer Eastep ◽  
Yang Li ◽  
...  
Keyword(s):  
Glucose Metabolism ◽  
Vitamin A ◽  
Insulin Receptor ◽  
High Fat Diet ◽  
Glycogen Synthase ◽  
Mitogen Activated Protein Kinase ◽  
High Fat ◽  
Expression Levels ◽  
Hepatic Expression ◽  
Hepatic Glucose

Whether vitamin A (VA) has a role in the development of metabolic abnormalities associated with intake of a high-fat diet (HFD) is unclear. Sprague–Dawley rats after weaning were fed an isocaloric VA sufficient HFD (VAS-HFD) or a VA deficient HFD (VAD-HFD) for 8 weeks. Body mass, food intake, liver and adipose tissue mass, and the hepatic expression levels of key proteins for metabolism were determined. VAD-HFD rats had lower body, liver, and epididymal fat mass than VAS-HFD rats. VAD-HFD rats had lower hepatic protein expression levels of cytochrome P450 26A1, glucokinase, and phosphoenolpyruvate carboxykinase than VAS-HFD rats. VAD-HFD rats had higher protein levels of glycogen synthase kinase (GSK)-3α and lower levels of GSK-3β, but not glycogen synthase, than VAS-HFD rats. VAD-HFD rats had higher hepatic levels of insulin receptor substrate-1 (IRS-1), insulin receptor β-subunit, mitogen-activated protein kinase proteins, and peroxisome proliferator-activated receptor-gamma coactivator 1α mRNA, and lower level of IRS-2 protein than VAS-HFD rats. These results indicate that in a HFD setting, VA deficiency attenuated HFD-induced obesity, and VA status altered the expression levels of proteins required for glucose metabolism and insulin signaling. We conclude that VA status contributes to the regulation of hepatic glucose and lipid metabolism in a HFD setting, and may regulate hepatic carbohydrate metabolism.

scholarly journals Mouse models of hereditary hemochromatosis do not develop early liver fibrosis in response to a high fat diet

2018 ◽  
Author(s):  
John Wagner ◽  
Carine Fillebeen ◽  
Tina Haliotis ◽  
Jeannie Mui ◽  
Hojatollah Vali ◽  
...  
Keyword(s):  
Liver Disease ◽  
Liver Fibrosis ◽  
Liver Injury ◽  
Iron Overload ◽  
Mouse Models ◽  
High Fat Diet ◽  
Hereditary Hemochromatosis ◽  
Regulatory Function ◽  
High Fat ◽  
Ultrastructural Studies

AbstractHepatic iron overload, a hallmark of hereditary hemochromatosis (HH), triggers progressive liver disease. There is also increasing evidence for a pathogenic role of iron in non-alcoholic fatty liver disease (NAFLD), which may progress to non-alcoholic steatohepatitis (NASH), fibrosis, cirrhosis and hepatocellular cancer. Mouse models of HH and NAFLD can be used to explore potential interactions between iron and lipid metabolic pathways. Hfe−/− mice, a model of moderate iron overload, were reported to develop early liver fibrosis in response to a high fat diet. However, this was not the case with Hjv−/− mice, a model of severe iron overload. These data raised the possibility that the Hfe gene may protect against liver injury independently of its iron regulatory function. Herein, we addressed this hypothesis in a comparative study utilizing wild type, Hfe−/−, Hjv−/− and double Hfe−/−Hjv−/− mice. The animals, all in C57/BL6 background, were fed with a high fat diet for 14 weeks and developed hepatic steatosis, associated with mild iron overload. Hfe co-ablation did not sensitize steatotic Hjv-deficient mice to liver injury. Moreover, we did not observe any signs of liver inflammation or fibrosis even in single steatotic Hfe−/− mice. Ultrastructural studies revealed a reduced lipid and glycogen content in Hjv−/− hepatocytes, indicative of a metabolic defect. Interestingly, glycogen levels were restored in double Hfe−/−Hjv−/− mice, which is consistent with a metabolic function of Hfe. We conclude that hepatocellular iron excess does not aggravate diet-induced steatosis to steatohepatitis or early liver fibrosis in mouse models of HH, irrespectively of the presence or lack of Hfe.

scholarly journals Deficiency of Cathelicidin Attenuates High-Fat Diet Plus Alcohol-Induced Liver Injury through FGF21/Adiponectin Regulation

Cells ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 3333
Author(s):  
Fengyuan Li ◽  
Jenny Chen ◽  
Yunhuan Liu ◽  
Zelin Gu ◽  
Mengwei Jiang ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Alcohol Consumption ◽  
Liver Injury ◽  
High Fat Diet ◽  
Uncoupling Protein ◽  
Neutrophil Infiltration ◽  
Hormone Sensitive Lipase ◽  
Fibroblast Growth Factor 21 ◽  
High Fat ◽  
Brown Adipose

Alcohol consumption and obesity are known risk factors of steatohepatitis. Here, we report that the deficiency of CRAMP (cathelicidin-related antimicrobial peptide—gene name: Camp) is protective against a high-fat diet (HFD) plus acute alcohol (HFDE)-induced liver injury. HFDE markedly induced liver injury and steatosis in WT mice, which were attenuated in Camp–/– mice. Neutrophil infiltration was lessened in the liver of Camp–/– mice. HFDE feeding dramatically increased epididymal white adipose tissue (eWAT) mass and induced adipocyte hypertrophy in WT mice, whereas these effects were attenuated by the deletion of Camp. Furthermore, Camp–/– mice had significantly increased eWAT lipolysis, evidenced by up-regulated expression of lipolytic enzymes, adipose triglyceride lipase (ATGL) and hormone-sensitive lipase (HSL). The depletion of Camp also increased uncoupling protein 1 (UCP1)-dependent thermogenesis in the brown adipose tissue (BAT) of mice. HFDE fed Camp–/– mice had elevated protein levels of fibroblast growth factor 21 (FGF21) in the eWAT, with an increased adiponectin production, which had been shown to alleviate hepatic fat deposition and inflammation. Collectively, we have demonstrated that Camp–/– mice are protected against HFD plus alcohol-induced liver injury and steatosis through FGF21/adiponectin regulation. Targeting CRAMP could be an effective approach for prevention/treatment of high-fat diet plus alcohol consumption-induced steatohepatitis.

Formononetin Ameliorates Cognitive Disorder via PGC-1α Pathway in Neuroinflammation Conditions in High-Fat Diet-Induced Mice

2019 ◽  
Vol 18 (7) ◽  
pp. 566-577 ◽  
Author(s):  
Xinxin Fu ◽  
Tingting Qin ◽  
Jiayu Yu ◽  
Jie Jiao ◽  
Zhanqiang Ma ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
High Fat Diet ◽  
Trifolium Pratense ◽  
Amyloid Β ◽  
Cognitive Disorder ◽  
Mechanism Study ◽  
High Fat ◽  
Neuroprotective Effects ◽  
Underlying Mechanisms

Background: Alzheimer’s disease is one of the most common neurodegenerative diseases in many modern societies. The core pathogenesis of Alzheimer’s disease includes the aggregation of hyperphosphorylated Tau and abnormal Amyloid-β generation. In addition, previous studies have shown that neuroinflammation is one of the pathogenesis of Alzheimer’s disease. Formononetin, an isoflavone compound extracted from Trifolium pratense L., has been found to have various properties including anti-obesity, anti-inflammation, and neuroprotective effects. But there are very few studies on the treatment of Alzheimer’s disease with Formononetin. Objective: The present study focused on the protective activities of Formononetin on a high-fat dietinduced cognitive decline and explored the underlying mechanisms. Methods: Mice were fed with HFD for 10 weeks and intragastric administrated daily with metformin (300 mg/kg) and Formononetin (20 and 40 mg/kg). Results: We found that Formononetin (20, 40 mg/kg) significantly attenuated the learning and memory deficits companied by weight improvement and decreased the levels of blood glucose, total cholesterol and triglyceride in high-fat diet-induced mice. Meanwhile, we observed high-fat diet significantly caused the Tau hyperphosphorylation in the hippocampus of mice, whereas Formononetin reversed this effect. Additionally, Formononetin markedly reduced the levels of inflammation cytokines IL-1β and TNF-α in high-fat diet-induced mice. The mechanism study showed that Formononetin suppressed the pro-inflammatory NF-κB signaling and enhanced the anti-inflammatory Nrf-2/HO-1 signaling, which might be related to the regulation of PGC-1α in the hippocampus of high-fat diet -induced mice. Conclusion: Taken together, our results showed that Formononetin could improve the cognitive function by inhibiting neuroinflammation, which is attributed to the regulation of PGC-1α pathway in HFD-induced mice.

scholarly journals Gut Microbiome and Metabolome Profiles Associated with High-Fat Diet in Mice

Metabolites ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 482
Author(s):  
Jae-Kwon Jo ◽  
Seung-Ho Seo ◽  
Seong-Eun Park ◽  
Hyun-Woo Kim ◽  
Eun-Ju Kim ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Relative Abundance ◽  
High Fat Diet ◽  
Amplicon Sequencing ◽  
Gas Chromatography Mass Spectrometry ◽  
Control Group ◽  
Rrna Gene ◽  
High Fat ◽  
Underlying Mechanisms ◽  
Insight Into

Obesity can be caused by microbes producing metabolites; it is thus important to determine the correlation between gut microbes and metabolites. This study aimed to identify gut microbiota-metabolomic signatures that change with a high-fat diet and understand the underlying mechanisms. To investigate the profiles of the gut microbiota and metabolites that changed after a 60% fat diet for 8 weeks, 16S rRNA gene amplicon sequencing and gas chromatography-mass spectrometry (GC-MS)-based metabolomic analyses were performed. Mice belonging to the HFD group showed a significant decrease in the relative abundance of Bacteroidetes but an increase in the relative abundance of Firmicutes compared to the control group. The relative abundance of Firmicutes, such as Lactococcus, Blautia, Lachnoclostridium, Oscillibacter, Ruminiclostridium, Harryflintia, Lactobacillus, Oscillospira, and Erysipelatoclostridium, was significantly higher in the HFD group than in the control group. The increased relative abundance of Firmicutes in the HFD group was positively correlated with fecal ribose, hypoxanthine, fructose, glycolic acid, ornithine, serum inositol, tyrosine, and glycine. Metabolic pathways affected by a high fat diet on serum were involved in aminoacyl-tRNA biosynthesis, glycine, serine and threonine metabolism, cysteine and methionine metabolism, glyoxylate and dicarboxylate metabolism, and phenylalanine, tyrosine, and trypto-phan biosynthesis. This study provides insight into the dysbiosis of gut microbiota and metabolites altered by HFD and may help to understand the mechanisms underlying obesity mediated by gut microbiota.

FPS-ZM1 Alleviates Circulating Indices of Liver Injury in Diet-Induced Type 2 Diabetic Mice

2022 ◽  
Author(s):  
Somayeh Aslani ◽  
Saman Bahrambeigi ◽  
Davoud Sanajou
Keyword(s):  
Liver Injury ◽  
High Fat Diet ◽  
Lifestyle Modification ◽  
Serum Levels ◽  
Diabetic Mice ◽  
High Fat ◽  
Lifestyle Modifications ◽  
Gamma Glutamyl Transpeptidase ◽  
Alcoholic Fatty Liver

Despite dietary/lifestyle modifications as well as glycemic and lipid control, non-alcoholic fatty liver disease (NAFLD) imposes a considerable risk to the patients by advancing to non-alcoholic steatohepatitis (NASH). The present investigation aims to evaluate the protective potential of FPS-ZM1, a selective inhibitor for advanced glycation end products (RAGE), against circulating indices of liver injury in high fat diet-induced diabetic mice. FPS-ZM1 at 0.5. 1, and 2 mg/kg (orally) was administered for 2 months, starting 4 months after provision of the high-fat diet. Tests for glucose homeostasis, liver injury markers, and hepatic/plasma miR-21 expressions were performed. FPS-ZM1 attenuated diabetes-induced elevations in serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), glutamate dehydrogenase (GLD), and alpha glutathione-S-transferase (α-GST) as well as alkaline phosphatase (ALP) and gamma-glutamyl transpeptidase (GGT). It also decreased diabetes-associated elevations in serum ferritin and plasma cytokeratin 18 fragments. Additionally, FPS-ZM1 down-regulated elevated expressions of miR-21 in the liver and plasma of diabetic mice. These findings highlight the benefits of FPS-ZM in alleviating liver injury in mice evoked by high-fat diet-induced type 2 diabetes and suggest FPS-ZM1 as a new potential adjunct to the conventional diet/lifestyle modification and glycemic control in diabetics.

scholarly journals Contributions of a high-fat diet to Alzheimer's disease-related decline: A longitudinal behavioural and structural neuroimaging study in mouse models

2019 ◽  
Vol 21 ◽  
pp. 101606 ◽  
Author(s):  
Colleen P.E. Rollins ◽  
Daniel Gallino ◽  
Vincent Kong ◽  
Gülebru Ayranci ◽  
Gabriel A. Devenyi ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Models ◽  
High Fat Diet ◽  
High Fat ◽  
Structural Neuroimaging ◽  
Neuroimaging Study
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