scholarly journals High fat diet induces dysregulation of hepatic oxygen gradients and mitochondrial function in vivo

2008 ◽  
Vol 417 (1) ◽  
pp. 183-193 ◽  
Author(s):  
Sudheer K. Mantena ◽  
Denty Paul Vaughn ◽  
Kelly K. Andringa ◽  
Heather B. Eccleston ◽  
Adrienne L. King ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
High Fat Diet ◽  
Protein Modification ◽  
Control Diet ◽  
Critical Role ◽  
Liver Mitochondria ◽  
Mitochondrial Proteins ◽  
High Fat ◽  
Alcoholic Fatty Liver

NAFLD (non-alcoholic fatty liver disease), associated with obesity and the cardiometabolic syndrome, is an important medical problem affecting up to 20% of western populations. Evidence indicates that mitochondrial dysfunction plays a critical role in NAFLD initiation and progression to the more serious condition of NASH (non-alcoholic steatohepatitis). Herein we hypothesize that mitochondrial defects induced by exposure to a HFD (high fat diet) contribute to a hypoxic state in liver and this is associated with increased protein modification by RNS (reactive nitrogen species). To test this concept, C57BL/6 mice were pair-fed a control diet and HFD containing 35% and 71% total calories (1 cal≈4.184 J) from fat respectively, for 8 or 16 weeks and liver hypoxia, mitochondrial bioenergetics, NO (nitric oxide)-dependent control of respiration, and 3-NT (3-nitrotyrosine), a marker of protein modification by RNS, were examined. Feeding a HFD for 16 weeks induced NASH-like pathology accompanied by elevated triacylglycerols, increased CYP2E1 (cytochrome P450 2E1) and iNOS (inducible nitric oxide synthase) protein, and significantly enhanced hypoxia in the pericentral region of the liver. Mitochondria from the HFD group showed increased sensitivity to NO-dependent inhibition of respiration compared with controls. In addition, accumulation of 3-NT paralleled the hypoxia gradient in vivo and 3-NT levels were increased in mitochondrial proteins. Liver mitochondria from mice fed the HFD for 16 weeks exhibited depressed state 3 respiration, uncoupled respiration, cytochrome c oxidase activity, and mitochondrial membrane potential. These findings indicate that chronic exposure to a HFD negatively affects the bioenergetics of liver mitochondria and this probably contributes to hypoxic stress and deleterious NO-dependent modification of mitochondrial proteins.

scholarly journals MicroRNA-29a Suppresses CD36 to Ameliorate High Fat Diet-Induced Steatohepatitis and Liver Fibrosis in Mice

Cells ◽  
2019 ◽  
Vol 8 (10) ◽  
pp. 1298 ◽  
Author(s):  
Hung-Yu Lin ◽  
Feng-Sheng Wang ◽  
Ya-Ling Yang ◽  
Ying-Hsien Huang
Keyword(s):  
Transcription Factor ◽  
Liver Fibrosis ◽  
High Fat Diet ◽  
Critical Role ◽  
Luciferase Reporter ◽  
Hepatic Tissue ◽  
Wild Type ◽  
High Fat ◽  
Alcoholic Fatty Liver ◽  
Mesenchymal Transition

MicroRNA-29 (miR-29) has been shown to play a critical role in reducing inflammation and fibrosis following liver injury. Non-alcoholic fatty liver disease (NAFLD) occurs when fat is deposited (steatosis) in the liver due to causes other than excessive alcohol use and is associated with liver fibrosis. In this study, we asked whether miR-29a could reduce experimental high fat diet (HFD)-induced obesity and liver fibrosis in mice. We performed systematical expression analyses of miR-29a transgenic mice (miR-29aTg mice) and wild-type littermates subjected to HFD-induced NAFLD. The results demonstrated that increased miR-29a not only alleviated HFD-induced body weight gain but also subcutaneous, visceral, and intestinal fat accumulation and hepatocellular steatosis in mice. Furthermore, hepatic tissue in the miR-29aTg mice displayed a weak fibrotic matrix concomitant with low fibrotic collagen1α1 expression within the affected tissues compared to the wild-type (WT) mice fed the HFD diet. Increased miR-29a signaling also resulted in the downregulation of expression of the epithelial mesenchymal transition-executing transcription factor snail, mesenchymal markers vimentin, and such pro-inflammation markers as il6 and mcp1 within the liver tissue. Meanwhile, miR-29aTg-HFD mice exhibited significantly lower levels of peroxisome proliferator-activated receptor γ (PPARγ), mitochondrial transcription factor A TFAM, and mitochondria DNA content in the liver than the WT-HFD mice. An in vitro luciferase reporter assay further confirmed that miR-29a mimic transfection reduced fatty acid translocase CD36 expression in HepG2 cells. Conclusion: Our data provide new insights that miR-29a can improve HDF-induced obesity, hepatocellular steatosis, and fibrosis, as well as highlight the role of miR-29a in regulation of NAFLD.

Effect of a high-fat diet on the incorporation of stored triacylglycerol into hepatic VLDL

1992 ◽  
Vol 263 (4) ◽  
pp. E615-E623 ◽  
Author(s):  
O. L. Francone ◽  
G. Griffaton ◽  
A. D. Kalopissis
Keyword(s):  
Endoplasmic Reticulum ◽  
High Fat Diet ◽  
Lipid Droplets ◽  
Control Diet ◽  
Oxidation Products ◽  
High Fat ◽  
Very Low Density Lipoproteins ◽  
Total Utilization ◽  
Fat Feeding

Triacylglycerol (TG) stored in cytoplasmic lipid droplets of hepatocytes was labeled by in vivo [1-(14)C]oleic acid injection to study the effect of a high-fat diet on its incorporation into very-low-density lipoproteins (VLDL). Compared with the control diet, hepatocytes of fat-fed rats 1) contained 7.6 times more cytoplasmic (floating fat) TG and 1.9 times more endoplasmic reticulum (microsomal) TG; 2) had 8 and 6 times lower TG specific activities in cytoplasm and endoplasmic reticulum, respectively; 3) incorporated 22% less 14C label into hepatocyte esterified lipids (TG, cholesterol, phospholipid); 4) secreted 48 and 33% less radioactive and total VLDL-TG, respectively; 5) oxidized more cytoplasmic TG-fatty acid (FA); and 6) showed a 50% decreased total utilization of stored TG-FA. With both diets, the lysosomal inhibitor chloroquine concomitantly decreased productions of labeled VLDL-TG, CO2, and acid-soluble oxidation products. The decreased incorporation of stored TG into VLDL-TG appreciably contributes to the overall inhibition of hepatic VLDL secretion by fat feeding. It appears to be related to the decreased mobilization rate of stored TG and its increased channelling toward oxidation.

scholarly journals Muscular G9a regulates muscle-liver-fat axis by musclin under overnutrition in female mice

2020 ◽  
Author(s):  
Ada Admin ◽  
Wenquan Zhang ◽  
Dong Yang ◽  
Yangmian Yuan ◽  
Chong Liu ◽  
...  
Keyword(s):  
Hepatic Steatosis ◽  
High Fat Diet ◽  
Critical Role ◽  
Liver Fat ◽  
High Fat ◽  
Core Domain ◽  
Female Mice ◽  
Methylase Activity

Crosstalk among different tissues and organs is a hotspot in metabolic research. Recent studies have revealed the regulatory roles of a number of myokines in metabolism. Here, we report that female mice muscle-specific lacking histone methylase G9a (<i>Ehmt2</i><sup>Ckmm </sup>KO<i> </i>or <i>Ehmt2</i><sup>HSA</sup> KO) are resistant to high-fat-diet (HFD) induced obesity and hepatic steatosis. Furthermore, we identified significantly upregulated circulating level of musclin, a myokine, in HFD-fed <i>Ehmt2</i><sup>Ckmm </sup>KO or <i>Ehmt2</i><sup>HSA</sup> KO female mice. Similarly, upregulated musclin was observed in mice injected with two structurally different inhibitors for G9a methylase activity, BIX01294 and A366. Moreover, injection of recombinant full-length musclin or its functional core domain, inhibited the HFD-induced obesity and hepatic steatosis in wildtype female and male mice. Mechanistically, G9a methylase activity-dependently regulated muscular musclin level by binding to its promoter, also by regulating p-Foxo1/Foxo1 level <i>in vivo</i> and <i>in vitro</i>. Collectively, these data suggested a critical role for G9a in the ‘muscle-liver-fat’ metabolic axis, at least for female mice. Musclin may serve as a potential therapeutic candidate for obesity and associated diseases.

scholarly journals Sanziguben polysaccharides inhibit diabetic nephropathy through NF-κB-mediated anti-inflammation

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Kang Zhou ◽  
Jianing Zhang ◽  
Chang Liu ◽  
Lijuan Ou ◽  
Fan Wang ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
High Fat Diet ◽  
In Vitro Model ◽  
Critical Role ◽  
High Fat ◽  
Chinese Medicines ◽  
Vitro Model ◽  
Anti Inflammation

Abstract Background Sanziguben polysaccharides (SZP) are large amounts of classical Chinese medicines from Sanziguben (SZGB). Moreover, SZGB is a widely applied compound prescription for diabetic nephropathy (DN) treatment, but the role is still unclear. This study initially explores the mechanism of SZP in the treatment of DN. Methods The high-fat diet plus streptozotocin injections were used to replicate the DN models in male C57BL/6 mice. DN mice were divided into five groups: DN mice, DN mice treated with SZP(1.01 or 2.02 g/kg), DN mice treated with SZGB decoction(4.7 g/kg), and DN mice treated with metformin (300 mg/kg). HG and LPS plus TNFα stimulated human tubule epithelial (HK-2) cells to establish an in vitro model and treated with SZP (100 or 200 μg/mL). Results SZP was found to comprise sugar, protein, and uronic acid. Furthermore, SZP alleviated the progression of inflammation in vivo and in vitro by inhibiting the expression of NF-κB. Conclusions NF-κB plays a critical role in the development of DN induced by STZ and HG. Furthermore, SZP can attenuate the NF-κB‐mediated progression of diabetic nephropathy, improve DN through anti-inflammation.

The short-term consumption of a moderately high-fat diet alters nitric oxide bioavailability in lean female Zucker rats

2011 ◽  
Vol 89 (4) ◽  
pp. 245-257 ◽  
Author(s):  
Kan Huang ◽  
Yue Huang ◽  
Jessica Frankel ◽  
Cassandra Addis ◽  
Lavina Jaswani ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
High Fat Diet ◽  
Control Diet ◽  
Zucker Rats ◽  
Kidney Cortex ◽  
No Production ◽  
High Fat ◽  
Enos Expression ◽  
Short Term ◽  
Indirect Measure

To determine whether short-term consumption of a moderately high-fat diet (MHFD) affects nitric oxide (NO) production, the concentration of stable NO metabolites (NOx) in urine and plasma of rats fed a MHFD (15.6 %g fat) or control diet (4.5 %g fat) was measured weekly for 4 weeks. Plasma and urine NOx levels were significantly depressed in the MHFD group by week 1 and remained so for the duration of the study. Decreased NO bioavailability may result from a decrease in NO production or the scavenging of NO by reactive oxygen species (ROS). Because endothelial NOS (eNOS) is the major contributor to NO production and circulating levels of NOx, eNOS expression was measured in several tissues. At week 1, there was a MHFD-associated decrease in eNOS expression in the liver. Subsequently, eNOS expression declined in the heart and kidney medulla of MHFD-fed rats at weeks 3 and 4, respectively. The expression of eNOS in the kidney cortex and adipose tissue did not change. These results suggest that a MHFD alters eNOS expression in a time-dependent and tissue-specific manner. In the liver, NOS activity and tissue levels of NOx and nitrotyrosine were measured. Nitrotyrosine levels were used as an indirect measure of the NO scavenged by ROS. There was a decrease in NOS activity, suggesting that the low levels of hepatic NOx were due, in part, to a decrease in NO production. In addition, there was a dramatic increase in nitrotyrosine formation, suggesting that the decline in hepatic NOx was also due to an increased interaction of NO with ROS. Tyrosine nitration commonly has detrimental effects on proteins. The decrease in NO and increase in protein nitration could potentially have adverse effects on tissue function.

scholarly journals Endothelial TFEB (Transcription Factor EB) Improves Glucose Tolerance via Upregulation of IRS (Insulin Receptor Substrate) 1 and IRS2

2020 ◽  
Author(s):  
Jinjian Sun ◽  
Haocheng Lu ◽  
Wenying Liang ◽  
Guizhen Zhao ◽  
Lu Ren ◽  
...  
Keyword(s):  
Glucose Tolerance ◽  
Transgenic Mice ◽  
High Fat Diet ◽  
Metabolic Diseases ◽  
Critical Role ◽  
Insulin Receptor Substrate ◽  
High Fat ◽  
Transcription Factor Eb

Objective: Vascular endothelial cells (ECs) play a critical role in maintaining vascular homeostasis. Aberrant EC metabolism leads to vascular dysfunction and metabolic diseases. TFEB (transcription factor EB), a master regulator of lysosome biogenesis and autophagy, has protective effects on vascular inflammation and atherosclerosis. However, the role of endothelial TFEB in metabolism remains to be explored. In this study, we sought to investigate the role of endothelial TFEB in glucose metabolism and underlying molecular mechanisms. Approach and Results: To determine whether endothelial TFEB is critical for glucose metabolism in vivo, we utilized EC-selective TFEB knockout and EC-selective TFEB transgenic mice fed a high-fat diet. EC-selective TFEB knockout mice exhibited significantly impaired glucose tolerance compared with control mice. Consistently, EC-selective TFEB transgenic mice showed improved glucose tolerance. In primary human ECs, small interfering RNA-mediated TFEB knockdown blunts Akt (AKT serine/threonine kinase) signaling. Adenovirus-mediated overexpression of TFEB consistently activates Akt and significantly increases glucose uptake in ECs. Mechanistically, TFEB upregulates IRS1 and IRS2 (insulin receptor substrate 1 and 2). TFEB increases IRS2 transcription measured by reporter gene and chromatin immunoprecipitation assays. Furthermore, we found that TFEB increases IRS1 protein via downregulation of microRNAs (miR-335, miR-495, and miR-548o). In vivo, Akt signaling in the skeletal muscle and adipose tissue was significantly impaired in EC-selective TFEB knockout mice and consistently improved in EC-selective TFEB transgenic mice on high-fat diet. Conclusions: Our data revealed a critical role of TFEB in endothelial metabolism and suggest that TFEB constitutes a potential molecular target for the treatment of vascular and metabolic diseases.

scholarly journals LPIAT1/MBOAT7 depletion increases triglyceride synthesis fueled by high phosphatidylinositol turnover

Gut ◽  
2020 ◽  
Vol 70 (1) ◽  
pp. 180-193 ◽  
Author(s):  
Yuki Tanaka ◽  
Yuta Shimanaka ◽  
Andrea Caddeo ◽  
Takuya Kubo ◽  
Yanli Mao ◽  
...  
Keyword(s):  
Knockout Mice ◽  
High Fat Diet ◽  
Acyl Chain ◽  
High Fat ◽  
Triglyceride Synthesis ◽  
Alcoholic Fatty Liver ◽  
Hepatic Cells ◽  
Triglyceride Accumulation ◽  
Lipid Species

ObjectiveNon-alcoholic fatty liver disease (NAFLD) is a common prelude to cirrhosis and hepatocellular carcinoma. The genetic rs641738 C>T variant in the lysophosphatidylinositol acyltransferase 1 (LPIAT1)/membrane bound O-acyltransferase domain-containing 7, which incorporates arachidonic acid into phosphatidylinositol (PI), is associated with the entire spectrum of NAFLD. In this study, we investigated the mechanism underlying this association in mice and cultured human hepatocytes.DesignWe generated the hepatocyte-specific Lpiat1 knockout mice to investigate the function of Lpiat1 in vivo. We also depleted LPIAT1 in cultured human hepatic cells using CRISPR-Cas9 systems or siRNA. The effect of LPIAT1-depletion on liver fibrosis was examined in mice fed high fat diet and in liver spheroids. Lipid species were measured using liquid chromatography-electrospray ionisation mass spectrometry. Lipid metabolism was analysed using radiolabeled glycerol or fatty acids.ResultsThe hepatocyte-specific Lpiat1 knockout mice developed hepatic steatosis spontaneously, and hepatic fibrosis on high fat diet feeding. Depletion of LPIAT1 in cultured hepatic cells and in spheroids caused triglyceride accumulation and collagen deposition. The increase in hepatocyte fat content was due to a higher triglyceride synthesis fueled by a non-canonical pathway. Indeed, reduction in the PI acyl chain remodelling caused a high PI turnover, by stimulating at the same time PI synthesis and breakdown. The degradation of PI was mediated by a phospholipase C, which produces diacylglycerol, a precursor of triglyceride.ConclusionWe found a novel pathway fueling triglyceride synthesis in hepatocytes, by a direct metabolic flow of PI into triglycerides. Our findings provide an insight into the pathogenesis and therapeutics of NAFLD.

scholarly journals Muscular G9a regulates muscle-liver-fat axis by musclin under overnutrition in female mice

2020 ◽  
Author(s):  
Ada Admin ◽  
Wenquan Zhang ◽  
Dong Yang ◽  
Yangmian Yuan ◽  
Chong Liu ◽  
...  
Keyword(s):  
Hepatic Steatosis ◽  
High Fat Diet ◽  
Critical Role ◽  
Liver Fat ◽  
High Fat ◽  
Core Domain ◽  
Female Mice ◽  
Methylase Activity

Crosstalk among different tissues and organs is a hotspot in metabolic research. Recent studies have revealed the regulatory roles of a number of myokines in metabolism. Here, we report that female mice muscle-specific lacking histone methylase G9a (<i>Ehmt2</i><sup>Ckmm </sup>KO<i> </i>or <i>Ehmt2</i><sup>HSA</sup> KO) are resistant to high-fat-diet (HFD) induced obesity and hepatic steatosis. Furthermore, we identified significantly upregulated circulating level of musclin, a myokine, in HFD-fed <i>Ehmt2</i><sup>Ckmm </sup>KO or <i>Ehmt2</i><sup>HSA</sup> KO female mice. Similarly, upregulated musclin was observed in mice injected with two structurally different inhibitors for G9a methylase activity, BIX01294 and A366. Moreover, injection of recombinant full-length musclin or its functional core domain, inhibited the HFD-induced obesity and hepatic steatosis in wildtype female and male mice. Mechanistically, G9a methylase activity-dependently regulated muscular musclin level by binding to its promoter, also by regulating p-Foxo1/Foxo1 level <i>in vivo</i> and <i>in vitro</i>. Collectively, these data suggested a critical role for G9a in the ‘muscle-liver-fat’ metabolic axis, at least for female mice. Musclin may serve as a potential therapeutic candidate for obesity and associated diseases.

scholarly journals An in vivo reporter for tracking lipid droplet dynamics in transparent zebrafish

2020 ◽  
Author(s):  
Dianne Lumaquin ◽  
Eleanor Johns ◽  
Joshua Weiss ◽  
Emily Montal ◽  
Olayinka Ooladipupo ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Lipid Droplet ◽  
High Fat Diet ◽  
Lipid Droplets ◽  
Cell Types ◽  
Structural Protein ◽  
High Fat ◽  
Droplet Dynamics ◽  
Perilipin 2

AbstractLipid droplets are lipid storage organelles found in nearly all cell types from adipocytes to cancer cells. Although increasingly implicated in disease, current methods to study lipid droplets require fixation or static imaging which limits investigation of their rapid in vivo dynamics. To address this, we created a lipid droplet transgenic reporter in whole animals and cell culture by fusing tdTOMATO to Perilipin-2 (PLIN2), a lipid droplet structural protein. Expression of this transgene in transparent casper zebrafish enabled in vivo imaging of adipose depots responsive to nutrient deprivation and high-fat diet. Using this system, we tested novel regulators of lipolysis, revealing an unexpected role for nitric oxide in modulating adipocyte lipid droplets. Similarly, we expressed the PLIN2-tdTOMATO transgene in melanoma cells and found that the nitric oxide pathway also regulated lipid droplets in cancer. This model offers a tractable imaging platform to study lipid droplets across cell types and disease contexts.

Integrative study of diet-induced mouse models of NAFLD identifies PPARα as a sexually dimorphic drug target

Gut ◽  
2021 ◽  
pp. gutjnl-2020-323323
Author(s):  
Sarra Smati ◽  
Arnaud Polizzi ◽  
Anne Fougerat ◽  
Sandrine Ellero-Simatos ◽  
Yuna Blum ◽  
...  
Keyword(s):  
Gene Expression ◽  
High Fat Diet ◽  
Large Scale ◽  
Expression Profiles ◽  
Control Diet ◽  
Western Diet ◽  
Specific Response ◽  
Sexually Dimorphic ◽  
High Fat ◽  
Alcoholic Fatty Liver

ObjectiveWe evaluated the influence of sex on the pathophysiology of non-alcoholic fatty liver disease (NAFLD). We investigated diet-induced phenotypic responses to define sex-specific regulation between healthy liver and NAFLD to identify influential pathways in different preclinical murine models and their relevance in humans.DesignDifferent models of diet-induced NAFLD (high-fat diet, choline-deficient high-fat diet, Western diet or Western diet supplemented with fructose and glucose in drinking water) were compared with a control diet in male and female mice. We performed metabolic phenotyping, including plasma biochemistry and liver histology, untargeted large-scale approaches (liver metabolome, lipidome and transcriptome), gene expression profiling and network analysis to identify sex-specific pathways in the mouse liver.ResultsThe different diets induced sex-specific responses that illustrated an increased susceptibility to NAFLD in male mice. The most severe lipid accumulation and inflammation/fibrosis occurred in males receiving the high-fat diet and Western diet, respectively. Sex-biased hepatic gene signatures were identified for these different dietary challenges. The peroxisome proliferator-activated receptor α (PPARα) co-expression network was identified as sexually dimorphic, and in vivo experiments in mice demonstrated that hepatocyte PPARα determines a sex-specific response to fasting and treatment with pemafibrate, a selective PPARα agonist. Liver molecular signatures in humans also provided evidence of sexually dimorphic gene expression profiles and the sex-specific co-expression network for PPARα.ConclusionsThese findings underscore the sex specificity of NAFLD pathophysiology in preclinical studies and identify PPARα as a pivotal, sexually dimorphic, pharmacological target.Trial registration numberNCT02390232.

Sign in / Sign up

Export Citation Format

Share Document