scholarly journals Obesity progression causes liver steatosis and co-morbidities without apparent cardiac metabolic and functional decline

2021 ◽  
Vol 14 (8) ◽  
Author(s):  
André Ferreira do Nascimento ◽  
Aline de Oliveira Martins ◽  
Tamiris Aparecida Souza de Oliveira ◽  
Camila Renata Correa ◽  
Katashi Okoshi ◽  
...  
Keyword(s):  
Hepatic Steatosis ◽  
Functional Decline ◽  
Liver Steatosis ◽  
Plasma Free Fatty Acid ◽  
Cardiac Metabolism ◽  
Western Diet ◽  
Chow Diet ◽  
Mrna Levels ◽  
Male Wistar Rats ◽  
And Function

The goal of this study was to test if obesity progression can be a risk factor to alter cardiac metabolism and function along the time. Male Wistar rats were randomly divided to receive either chow diet (12.0% calories from fat) [C group] or high-fat diet (49.7% calories from fat) plus sucrose in the drinking water (100% from carbohydrate) [H group] for 6, 12 and 24 weeks. The Western diet significantly increased adiposity index of rats in all three experimental periods compared to C group. This was associated with increased plasma levels of insulin, resistin, leptin, glucose, triacylglycerol and decreased adiponectin, however, all variables were stable along the time except insulin and leptin. Plasma free fatty acid was only elevated with 24 weeks treatment. The obesity status resulted in hepatic steatosis progression in H group, while oxidative stress, hepatic inflammatory foci as well as TNF-α and IL-6 mRNA levels were not affected. There are no cardiac performance decline as well as metabolism cardiac changes in H group when compared with C. In conclusion, Western diet induced and promoted obesity, co-morbidities and hepatic steatosis progression while was not associated with apparent alterations of cardiac metabolism and function. These results suggest that obesity progression seems to affect the organs of distinct ways, and cardiac dysfunction is a question of time

scholarly journals Human GDPD3 overexpression promotes liver steatosis by increasing lysophosphatidic acid production and fatty acid uptake

2020 ◽  
Vol 61 (7) ◽  
pp. 1075-1086 ◽  
Author(s):  
Chia-Chi C. Key ◽  
Andrew C. Bishop ◽  
Xianfeng Wang ◽  
Qingxia Zhao ◽  
Guan-yuan Chen ◽  
...  
Keyword(s):  
Hepatic Steatosis ◽  
Liver Steatosis ◽  
Fatty Acid Uptake ◽  
Western Diet ◽  
Acid Uptake ◽  
Mrna Levels ◽  
Glycerol Phosphate ◽  
Adeno Associated Virus ◽  
Mouse Hepatocytes ◽  
Tag Accumulation

The glycerol phosphate pathway produces more than 90% of the liver triacylglycerol (TAG). LysoPA, an intermediate in this pathway, is produced by glycerol-3-phosphate acyltransferase. Glycerophosphodiester phosphodiesterase domain containing 3 (GDPD3), whose gene was recently cloned, contains lysophospholipase D activity, which produces LysoPA from lysophospholipids. Whether human GDPD3 plays a role in hepatic TAG homeostasis is unknown. We hypothesized that human GDPD3 increases LysoPA production and availability in the glycerol phosphate pathway, promoting TAG biosynthesis. To test our hypothesis, we infected C57BL/6J mice with adeno-associated virus encoding a hepatocyte-specific albumin promoter that drives GFP (control) or FLAG-tagged human GDPD3 overexpression and fed the mice chow or a Western diet to induce hepatosteatosis. Hepatic human GDPD3 overexpression induced LysoPA production and increased FA uptake and incorporation into TAG in mouse hepatocytes and livers, ultimately exacerbating Western diet-induced liver steatosis. Our results also showed that individuals with hepatic steatosis have increased GDPD3 mRNA levels compared with individuals without steatosis. Collectively, these findings indicate that upregulation of GDPD3 expression may play a key role in hepatic TAG accumulation and may represent a molecular target for managing hepatic steatosis.

scholarly journals Western-diet consumption induces alteration of barrier function mechanisms in the ileum that correlates with metabolic endotoxemia in rats

2017 ◽  
Vol 313 (2) ◽  
pp. E107-E120 ◽  
Author(s):  
Mathilde Guerville ◽  
Anaïs Leroy ◽  
Annaëlle Sinquin ◽  
Fabienne Laugerette ◽  
Marie-Caroline Michalski ◽  
...  
Keyword(s):  
Gene Expression ◽  
Elevated Serum ◽  
Caloric Intake ◽  
Western Diet ◽  
Chow Diet ◽  
Low Grade ◽  
Mrna Levels ◽  
Intestinal Alkaline Phosphatase ◽  
Ad Libitum ◽  
Metabolic Endotoxemia

Obesity and its related disorders have been associated with the presence in the blood of gut bacteria-derived lipopolysaccharides (LPS). However, the factors underlying this low-grade elevation in plasma LPS, so-called metabolic endotoxemia, are not fully elucidated. We aimed to investigate the effects of Western diet (WD) feeding on intestinal and hepatic LPS handling mechanisms in a rat model of diet-induced obesity (DIO). Rats were fed either a standard chow diet (C) or a Western Diet (WD, 45% fat) for 6 wk. They were either fed ad libitum or pair-fed to match the caloric intake of C rats for the first week, then fed ad libitum for the remaining 5 wk. Six-week WD feeding led to a mild obese phenotype with increased adiposity and elevated serum LPS-binding protein (LBP) levels relative to C rats, irrespective of initial energy intake. Serum LPS was not different between dietary groups but exhibited strong variability. Disrupted ileal mucus secretion and decreased ileal Reg3-γ and -β gene expression along with high ileal permeability to LPS were observed in WD compared with C-fed rats. Ileal and cecal intestinal alkaline phosphatase (IAP) activity as well as Verrucomicrobia and Bifidobacterium cecal levels were increased in WD-fed rats compared with C-fed rats. WD consumption did not impact mRNA levels of LPS-handling hepatic enzymes. Correlation analysis revealed that ileal passage of LPS, IAP activity, Proteobacteria levels and hepatic aoah gene expression correlated with serum LPS and LBP, suggesting that ileal mucosal defense impairment induced by WD feeding contribute to metabolic endotoxemia.

scholarly journals Petite Integration Factor 1 (PIF1) helicase deficiency increases weight gain in Western diet-fed female mice without increased inflammatory markers or decreased glucose clearance

2018 ◽  
Author(s):  
Frances R. Belmonte ◽  
Nikolaos Dedousis ◽  
Ian Sipula ◽  
Nikita A. Desai ◽  
Aatur D. Singhi ◽  
...  
Keyword(s):  
Gene Expression ◽  
Weight Gain ◽  
Hepatic Steatosis ◽  
Inflammatory Markers ◽  
Western Diet ◽  
Metabolic Phenotype ◽  
Whole Body ◽  
Chow Diet ◽  
Female Mice ◽  
Glucose Clearance

AbstractPetite Integration Factor 1 (PIF1) is a multifunctional helicase present in nuclei and mitochondria. PIF1 knock out (KO) mice exhibit accelerated weight gain and decreased wheel running on a normal chow diet. In the current study, we investigated whether Pif1 removal alters whole body metabolism in response to weight gain. PIF1 KO and wild type (WT) C57BL/6J mice were fed a Western diet (WD) rich in fat and carbohydrates before evaluation of their metabolic phenotype. Compared with weight gain-resistant WT female mice, WD-fed PIF1 KO females, but not males, showed accelerated adipose deposition, decreased locomotor activity, and reduced whole-body energy expenditure without increased dietary intake. Surprisingly, PIF1 KO females were protected against obesity-induced alterations in fasting blood glucose and glucose clearance. WD-fed PIF1 KO females developed mild hepatic steatosis and associated changes in liver gene expression that were absent in weight-matched, WD-fed female controls, linking hepatic steatosis to Pif1 ablation rather than increased body weight. WD-fed PIF1 KO females also showed decreased gene expression of inflammatory markers in adipose tissue. Collectively, these data separated weight gain from inflammation and impaired glucose homeostasis. They also support a role for Pif1 in weight gain resistance and liver metabolic dysregulation during nutrient stress.

scholarly journals Inhibition of Atherosclerosis and Liver Steatosis by Agmatine in Western Diet-Fed apoE-Knockout Mice Is Associated with Decrease in Hepatic De Novo Lipogenesis and Reduction in Plasma Triglyceride/High-Density Lipoprotein Cholesterol Ratio

2021 ◽  
Vol 22 (19) ◽  
pp. 10688
Author(s):  
Anna Wiśniewska ◽  
Aneta Stachowicz ◽  
Katarzyna Kuś ◽  
Magdalena Ulatowska-Białas ◽  
Justyna Totoń-Żurańska ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Hepatic Steatosis ◽  
De Novo ◽  
Therapeutic Potential ◽  
Liver Steatosis ◽  
Western Diet ◽  
De Novo Lipogenesis ◽  
Acid Oxidation ◽  
Cholesterol Ratio ◽  
Triglyceride Accumulation

Atherosclerosis and NAFLD are the leading causes of death worldwide. The hallmark of NAFLD is triglyceride accumulation caused by an imbalance between lipogenesis de novo and fatty acid oxidation. Agmatine, an endogenous metabolite of arginine, exerts a protective effect on mitochondria and can modulate fatty acid metabolism. In the present study, we investigate the influence of agmatine on the progression of atherosclerotic lesions and the development of hepatic steatosis in apoE−/− mice fed with a Western high-fat diet, with a particular focus on its effects on the DNL pathway in the liver. We have proved that treatment of agmatine inhibits the progression of atherosclerosis and attenuates hepatic steatosis in apoE−/− mice on a Western diet. Such effects are associated with decreased total macrophage content in atherosclerotic plaque as well as a decrease in the TG levels and the TG/HDL ratio in plasma. Agmatine also reduced TG accumulation in the liver and decreased the expression of hepatic genes and proteins involved in lipogenesis de novo such as SREBP-1c, FASN and SCD1. In conclusion, agmatine may present therapeutic potential for the treatment of atherosclerosis and fatty liver disease. However, an exact understanding of the mechanisms of the advantageous actions of agmatine requires further study.

scholarly journals Lactobacillus rhamnosus GG culture supernatant ameliorates acute alcohol-induced intestinal permeability and liver injury

2012 ◽  
Vol 303 (1) ◽  
pp. G32-G41 ◽  
Author(s):  
Yuhua Wang ◽  
Yanlong Liu ◽  
Anju Sidhu ◽  
Zhenhua Ma ◽  
Craig McClain ◽  
...  
Keyword(s):  
Liver Injury ◽  
Intestinal Permeability ◽  
Culture Supernatant ◽  
Ex Vivo ◽  
Liver Steatosis ◽  
Lactobacillus Rhamnosus ◽  
Intestinal Barrier ◽  
Chow Diet ◽  
Mrna Levels ◽  
Lactobacillus Rhamnosus Gg

Endotoxemia is a contributing cofactor to alcoholic liver disease (ALD), and alcohol-induced increased intestinal permeability is one of the mechanisms of endotoxin absorption. Probiotic bacteria have been shown to promote intestinal epithelial integrity and protect barrier function in inflammatory bowel disease (IBD) and in ALD. Although it is highly possible that some common molecules secreted by probiotics contribute to this action in IBD, the effect of probiotic culture supernatant has not yet been studied in ALD. We examined the effects of Lactobacillus rhamnosus GG culture supernatant (LGG-s) on the acute alcohol-induced intestinal integrity and liver injury in a mouse model. Mice on standard chow diet were supplemented with supernatant from LGG culture (109 colony-forming unit/mouse) for 5 days, and one dose of alcohol at 6 g/kg body wt was administered via gavage. Intestinal permeability was measured by FITC-FD-4 ex vivo. Alcohol-induced liver injury was examined by measuring the activity of alanine aminotransferase (ALT) in plasma, and liver steatosis was evaluated by triglyceride content and Oil Red O staining of the liver sections. LGG-s pretreatment restored alcohol-induced reduction in ileum mRNA levels of claudin-1, intestine trefoil factor (ITF), P-glycoprotein (P-gp), and cathelin-related antimicrobial peptide (CRAMP), which play important roles on intestinal barrier integrity. As a result, LGG-s pretreatment significantly inhibited the alcohol-induced intestinal permeability, endotoxemia and subsequently liver injury. Interestingly, LGG-s pretreatment increased ileum mRNA expression of hypoxia-inducible factor (HIF)-2α, an important transcription factor of ITF, P-gp, and CRAMP. These results suggest that LGG-s ameliorates the acute alcohol-induced liver injury by promoting HIF signaling, leading to the suppression of alcohol-induced increased intestinal permeability and endotoxemia. The use of bacteria-free LGG culture supernatant provides a novel strategy for prevention of acute alcohol-induced liver injury.

scholarly journals A Mineralocorticoid Receptor Deficiency in Myeloid Cells Reduces Liver Steatosis by Impairing Activation of CD8+ T Cells in a Nonalcoholic Steatohepatitis Mouse Model

2020 ◽  
Vol 11 ◽  
Author(s):  
Natalia Muñoz-Durango ◽  
Marco Arrese ◽  
Alejandra Hernández ◽  
Evelyn Jara ◽  
Alexis M. Kalergis ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Mineralocorticoid Receptor ◽  
Liver Steatosis ◽  
Costimulatory Molecule ◽  
Flow Cytometric Analysis ◽  
Myeloid Cells ◽  
Chow Diet ◽  
Mrna Levels ◽  
Deficient Diet

Background and AimsThe mineralocorticoid receptor (MR) and renin-angiotensin-aldosterone system (RAAS) are implicated in non-alcoholic liver fatty disease (NALFD). However, inflammatory mechanisms linking MR and RAAS with disease pathology remain unclear. Here we aimed to evaluate the contribution of myeloid MR to the inflammatory response in an animal model of non-alcoholic steatohepatitis (NASH), induced with a methionine-choline deficient diet (MCD).MethodsMice with a conditional deficiency of MR in myeloid cells (MyMRKO) and their counterpart floxed control mice (FC) were fed for 18 days with MCD or chow diet, respectively. Serum levels of aminotransferases and aldosterone levels were measured and hepatic steatosis, inflammation and fibrosis scored histologically. Hepatic triglyceride content (HTC) and hepatic mRNA levels of pro-inflammatory pro-fibrotic-associated genes were also assessed. Deep flow cytometric analysis was used to dissect the immune response during NASH development.ResultsMyMRKO mice fed with an MCD diet exhibited reduced hepatic inflammation and lower HTC than controls. Absolute number and percentage of liver inflammatory infiltrate cells (except for CD8+ T lymphocytes) were similar in both MyMRKO and control mice fed with an MCD diet but expression of the costimulatory molecule CD86 by dendritic cells and the CD25 activation marker in CD8+ T cells were significantly reduced in MyMRKO.ConclusionsProinflammatory cells are functionally suppressed in the absence of MR. We hypothesized that loss of MR in myeloid cells reduces lipid accumulation in the liver, in part through modulating the adaptive immune response, which is pivotal for the development of steatosis.

scholarly journals The Influence of Trehalose on Atherosclerosis and Hepatic Steatosis in Apolipoprotein E Knockout Mice

2019 ◽  
Vol 20 (7) ◽  
pp. 1552 ◽  
Author(s):  
Aneta Stachowicz ◽  
Anna Wiśniewska ◽  
Katarzyna Kuś ◽  
Anna Kiepura ◽  
Anna Gębska ◽  
...  
Keyword(s):  
Apolipoprotein E ◽  
Hepatic Steatosis ◽  
Molecular Mechanisms ◽  
Plasma Cholesterol ◽  
Liver Steatosis ◽  
Therapeutic Interventions ◽  
Prolonged Treatment ◽  
High Density Lipoproteins ◽  
Chow Diet ◽  
Apolipoprotein E Knockout Mice

Atherosclerosis and nonalcoholic fatty liver disease (NAFLD) are frequent causes of death in the Western countries. Recently, it has been shown that autophagy dysfunction plays an important role in the pathogenesis of both atherosclerosis and NAFLD; thus, activators of autophagy might be useful for novel therapeutic interventions. Trehalose—a naturally occuring disaccharide present in plants, bacteria, fungi, insects, and certain types of shrimps—is a known inducer of autophagy. However, according to the literature, its anti-atherosclerotic and anti-steatotic potential seem to depend on the experimental setting. The aim of our study was to comprehensively describe the influence of a prolonged treatment with orally administered trehalose on the development of atherosclerotic lesions and hepatic steatosis in apolipoprotein E knockout (apoE−/−) mice in an experimental set up reflecting both moderate and severe proatherogenic conditions: male apoE−/− mice on a chow diet (CD) and female apoE−/− mice fed with a high-fat diet (HFD). We found that exogenous trehalose inhibited atherosclerosis and attenuated hepatic steatosis in apoE−/− mice. Such effects of trehalose were not associated with changes of plasma cholesterol, low-density lipoproteins (LDL), or high-density lipoproteins (HDL). Moreover, the anti-steatotic action of trehalose in the liver was associated with the induction of autophagy. The exact molecular mechanisms of both the anti-atherosclerotic action of trehalose and its inhibitory effect on liver steatosis require further clarification.

scholarly journals Mice lacking adenosine 2A receptor reveal increased severity of MCD-induced NASH

2019 ◽  
Vol 243 (3) ◽  
pp. 199-209 ◽  
Author(s):  
Jing Zhou ◽  
Honggui Li ◽  
Yuli Cai ◽  
Linqiang Ma ◽  
Destiny Matthews ◽  
...  
Keyword(s):  
Hepatic Steatosis ◽  
Inflammatory Responses ◽  
Interleukin 1 ◽  
Chow Diet ◽  
Mrna Levels ◽  
Deficient Diet ◽  
Necrosis Factor Alpha ◽  
Alcoholic Fatty Liver ◽  
Adenosine 2A Receptor ◽  
And Control

Adenosine 2A receptor (A2AR) exerts a protective role in obesity-related non-alcoholic fatty liver disease. Here, we examined whether A2AR protects against non-alcoholic steatohepatitis (NASH). In C57BL/6J mice, feeding a methionine- and choline-deficient diet (MCD) resulted in significant weight loss, overt hepatic steatosis, and massive aggregation of macrophages in the liver compared with mice fed a chow diet. MCD feeding also significantly increased the numbers of A2AR-positive macrophages/Kupffer cells in liver sections although decreasing A2AR amount in liver lysates compared with chow diet feeding. Next, MCD-induced NASH phenotype was examined in A2AR-disrupted mice and control mice. Upon MCD feeding, A2AR-disruptd mice and control mice displayed comparable decreases in body weight and fat mass. However, MCD-fed A2AR-disrupted mice revealed greater liver weight and increased severity of hepatic steatosis compared with MCD-fed control mice. Moreover, A2AR-disupted mice displayed increased severity of MCD-induced liver inflammation, indicated by massive aggregation of macrophages and increased phosphorylation states of Jun-N terminal kinase (JNK) p46 and nuclear factor kappa B (NFκB) p65 and mRNA levels of tumor necrosis factor alpha, interleukin-1 beta, and interleukin-6. In vitro, incubation with MCD-mimicking media increased lipopolysaccharide (LPS)-induced phosphorylation states of JNK p46 and/or NFκB p65 and cytokine mRNAs in control macrophages and RAW264.7 cells, but not primary hepatocytes. Additionally, MCD-mimicking media significantly increased lipopolysaccharide-induced phosphorylation states of p38 and NFκB p65 in A2AR-deficient macrophages, but insignificantly decreased lipopolysaccharide-induced phosphorylation states of JNK p46 and NFκB p65 in A2AR-deficient hepatocytes. Collectively, these results suggest that A2AR disruption exacerbates MCD-induced NASH, which is attributable to, in large part, increased inflammatory responses in macrophages.

scholarly journals Beta vulgaris L. (Beetroot) Methanolic Extract Prevents Hepatic Steatosis and Liver Damage in T2DM Rats by Hypoglycemic, Insulin-Sensitizing, Antioxidant Effects, and Upregulation of PPARα

Biology ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 1306
Author(s):  
Laila Naif Al-Harbi ◽  
Ghedeir M. Alshammari ◽  
Alhanouf Mohammed Al-Dossari ◽  
Pandurangan Subash-Babu ◽  
Manal Abdulaziz Binobead ◽  
...  
Keyword(s):  
Hepatic Steatosis ◽  
Liver Damage ◽  
Body Weight Gain ◽  
Serum Levels ◽  
Serum Glucose ◽  
Mrna Levels ◽  
Hepatic Lipid Accumulation ◽  
Reduced Body ◽  
Male Wistar Rats ◽  
Factor Α

The present study examined if methanolic beetroot extract (BE) could prevent dyslipidemia and hepatic steatosis and damage in a type-2 diabetes mellitus (T2DM) rat model and studied some mechanisms of action. T2DM was induced in adult male Wistar rats by a low single dose of streptozotocin (STZ) (35 mg/kg, i.p) and a high-fat diet (HFD) feeding for 5 weeks. Control or T2DM rats then continued on standard or HFDs for another 12 weeks and were treated with the vehicle or BE (250 or 500 mg/kg). BE, at both doses, significantly improved liver structure and reduced hepatic lipid accumulation in the livers of T2DM rats. They also reduced body weight gain, serum glucose, insulin levels, serum and hepatic levels of cholesterol, triglycerides, free fatty acids, and serum levels of low-density lipoproteins in T2DM rats. In concomitant, they significantly reduced serum levels of aspartate and alanine aminotransferases, hepatic levels of malondialdehyde, tumor-necrosis factor-α, interleukin-6, and mRNA of Bax, cleaved caspase-3, and SREBP1/2. However, both doses of BE significantly increased hepatic levels of total glutathione, superoxide dismutase, and mRNA levels of Bcl2 and PPARα in the livers of both the control and T2DM rats. All of these effects were dose-dependent and more profound with doses of 500 mg/kg. In conclusion, chronic feeding of BE to STZ/HFD-induced T2DM in rats prevents hepatic steatosis and liver damage by its hypoglycemic and insulin-sensitizing effects and its ability to upregulate antioxidants and PPARα.

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