scholarly journals Reduced Liver Autophagy in High-Fat Diet Induced Liver Steatosis in New Zealand Obese Mice

Antioxidants ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 501
Author(s):  
Ioanna Korovila ◽  
Annika Höhn ◽  
Tobias Jung ◽  
Tilman Grune ◽  
Christiane Ott
Keyword(s):  
Lipid Droplet ◽  
High Fat Diet ◽  
Lipid Droplets ◽  
Liver Steatosis ◽  
Cellular Protein ◽  
Normal Function ◽  
High Fat ◽  
Alcoholic Fatty Liver ◽  
Lysosomal System ◽  
High Calorie

Non-alcoholic fatty liver disease (NAFLD), as a consequence of overnutrition caused by high-calorie diets, results in obesity and disturbed lipid homeostasis leading to hepatic lipid droplet formation. Lipid droplets can impair hepatocellular function; therefore, it is of utmost importance to degrade these cellular structures. This requires the normal function of the autophagic-lysosomal system and the ubiquitin-proteasomal system. We demonstrated in NZO mice, a polygenic model of obesity, which were compared to C57BL/6J (B6) mice, that a high-fat diet leads to obesity and accumulation of lipid droplets in the liver. This was accompanied by a loss of autophagy efficiency whereas the activity of lysosomal proteases and the 20S proteasome remained unaffected. The disturbance of cellular protein homeostasis was further demonstrated by the accumulation of 3-nitrotyrosine and 4-hydroxynonenal modified proteins, which are normally prone to degradation. Therefore, we conclude that fat accumulation in the liver due to a high-fat diet is associated with a failure of autophagy and leads to the disturbance of proteostasis. This might further contribute to lipid droplet stabilization and accumulation.

scholarly journals Integrated Transcriptomic and Translatomic Inquiry of the Role of Betaine on Lipid Metabolic Dysregulation Induced by a High-Fat Diet

2021 ◽  
Vol 8 ◽  
Author(s):  
Tengda Huang ◽  
Lin Yu ◽  
Hongyuan Pan ◽  
Zeqiang Ma ◽  
Tian Wu ◽  
...  
Keyword(s):  
Fatty Acid ◽  
High Fat Diet ◽  
Liver Lipid ◽  
Liver Steatosis ◽  
Enrichment Analysis ◽  
Gene Set Enrichment Analysis ◽  
Translational Efficiency ◽  
High Fat ◽  
Alcoholic Fatty Liver ◽  
Translational Level

An excessive high-fat/energy diet is a major cause of obesity and linked complications, such as non-alcoholic fatty liver disease (NAFLD). Betaine has been shown to effectively improve hepatic lipid metabolism. However, the mechanistic basis for this improvement is largely unknown. Herein, integration of mRNA sequencing and ribosome footprints profiling (Ribo-seq) was used to investigate the means by which betaine alleviates liver lipid metabolic disorders induced by a high-fat diet. For the transcriptome, gene set enrichment analysis demonstrated betaine to reduce liver steatosis by up-regulation of fatty acid beta oxidation, lipid oxidation, and fatty acid catabolic processes. For the translatome, 574 differentially expressed genes were identified, 17 of which were associated with the NAFLD pathway. By combined analysis of transcriptome and translatome, we found that betaine had the greater effect on NAFLD at the translational level. Further, betaine decreased translational efficiency (TE) for IDI1, CYP51A1, TM7SF2, and APOA4, which are related to lipid biosynthesis. In summary, this study demonstrated betaine alleviating lipid metabolic dysfunction at the translational level. The transcriptome and translatome data integration approach used herein provides for a new understanding of the means by which to treat NAFLD.

scholarly journals Modulating hepatocarcinogenesis by porto-systemic vein shunting in a high-fat diet mouse model

2021 ◽  
Vol 108 (Supplement_4) ◽  
Author(s):  
A Peloso ◽  
Q Gex ◽  
M Tihy ◽  
B Moeckli ◽  
F Slits ◽  
...  
Keyword(s):  
Mouse Model ◽  
Growth Pattern ◽  
High Fat Diet ◽  
Tumor Volume ◽  
Portal Pressure ◽  
Liver Steatosis ◽  
Common Disease ◽  
High Fat ◽  
Alcoholic Fatty Liver ◽  
Systemic Vein

Abstract Objective Non-alcoholic fatty liver disease (NAFLD) is an increasingly common disease, which can lead to hepatocellular carcinoma (HCC). It is associated with an increased portal pressure, which can alter the intestinal barrier, increase the translocation of bacterial products, and further worsen NAFLD. We hypothesized that this vicious circle can be broken by surgical porto-systemic vein shunting (PSVS), and previously demonstrated that PSVS can decrease the histological features of NAFLD in a high-fat diet (HFD) mouse model. We now test whether PSVS can also impact de-novo hepatocarcinogenesis. Methods C57BL/6 mice received HFD starting from 4 weeks of age. HCC was induced by intraperitoneal injection of DEN at 25mg/kg on week 2 and PSVS (n = 18) (or sham surgery (n = 18)) are created at 8 weeks. HCC burden was assessed by MRI and, finally, by macroscopic and histomorphology assessments. HCC features of aggressiveness, including solid growth pattern and fat component have been also evaluated. Results At 40 weeks of HFD feeding, tumors were identified in all the animals. Shunted HFD mice showed a reduced number of tumor nodules compared to sham (median nodules 8 vs 14, -42.9%; p = 0.0471) while associated to a greater average total tumor volume (709.3 vs 197 mm3, +258,6%; p = 0.0245). This correlated with an increased median tumor volume in shunted mice (16.30 vs 72.45 mm3, +344,5%; p = 0.0011). Notably, HCC histology of shunted mice was hallmarked by accentuated trend concerning HCC fatty change combined to a less pronounced solid growth pattern (p = 0.193). Conclusion PSVS leads to the presence of larger HCCs, potentially linked to the proportionally increased arterial supply of the liver. However, it demonstrates a protective effect on HCC carcinogenesis (< number of tumors). Collectively, this data suggests that portal pressure could represent a potential therapeutic target to attenuate liver steatosis and NAFLD-related HCC carcinogenesis.

scholarly journals Gut Microbiota Reshaped by Pectin Treatment Improves Liver Steatosis in Obese Mice

Nutrients ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 3725
Author(s):  
Camille Houron ◽  
Dragos Ciocan ◽  
Nicolas Trainel ◽  
Françoise Mercier-Nomé ◽  
Cindy Hugot ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
High Fat Diet ◽  
Liver Steatosis ◽  
Short Chain Fatty Acids ◽  
Fecal Microbiota ◽  
Soluble Fiber ◽  
High Fat ◽  
Alcoholic Fatty Liver ◽  
Induced Changes

Pectin, a soluble fiber, improves non-alcoholic fatty-liver disease (NAFLD), but its mechanisms are unclear. We aimed to investigate the role of pectin-induced changes in intestinal microbiota (IM) in NAFLD. We recovered the IM from mice fed a high-fat diet, treated or not with pectin, to perform a fecal microbiota transfer (FMT). Mice fed a high-fat diet, which induces NAFLD, were treated with pectin or received a fecal microbiota transfer (FMT) from mice treated with pectin before (preventive FMT) or after (curative FMT) being fed a high-fat diet. Pectin prevented the development of NAFLD, induced browning of adipose tissue, and modified the IM without increasing the abundance of proteobacteria. Preventive FMT also induced browning of white adipose tissue but did not improve liver steatosis, in contrast to curative FMT, which induced an improvement in steatosis. This was associated with an increase in the concentration of short-chain fatty acids (SCFAs), in contrast to preventive FMT, which induced an increase in the concentration of branched SCFAs. Overall, we show that the effect of pectin may be partially mediated by gut bacteria

scholarly journals Citrus Peel Extract Ameliorates High-Fat Diet-Induced NAFLD via Activation of AMPK Signaling

Nutrients ◽  
2020 ◽  
Vol 12 (3) ◽  
pp. 673 ◽  
Author(s):  
Geum-Hwa Lee ◽  
Cheng Peng ◽  
Seon-Ah Park ◽  
The-Hiep Hoang ◽  
Hwa-Young Lee ◽  
...  
Keyword(s):  
High Fat Diet ◽  
Liver Steatosis ◽  
The Elderly ◽  
Underlying Mechanism ◽  
Chow Diet ◽  
High Fat ◽  
Alcoholic Fatty Liver ◽  
Citrus Peel ◽  
Ampk Signaling ◽  
Normal Chow

Non-alcoholic fatty liver disease (NAFLD) is prevalent in the elderly population, and has symptoms ranging from liver steatosis to advanced fibrosis. Citrus peel extracts (CPEs) contain compounds that potentially improve dyslipidemia; however, the mechanism of action and effects on hepatic steatosis regulation remains unclear. Current study was aimed to investigate the protective effect of CPEs extracted through hot-air drying (CPEW) and freeze-drying (CPEF) and the underlying mechanism in a rat model of high-fat diet-induced NAFLD. The high-fat diet (HFD)-fed rats showed significant increase in total cholesterol, alanine aminotransferase (ALT), triglycerides, aspartate aminotransferase (AST), and lipid peroxidation compared to the normal chow-diet (NCD) group rats; but CPEW and CPEF limited this effect. CPEW and CPEF supplementation reduced both hepatocyte steatosis and fat accumulation involving the regulatory effect of mTORC1. Collectively, CPEW and CPEF protected deterioration of liver steatosis with AMPK activation and regulating ROS accumulation associated with interstitial disorders, which are also associated with endoplasmic reticulum (ER) redox. Thus, the application of CPEW and CPEF may lead to the development of novel therapeutic or preventive agents against NAFLD.

Beneficial effects of rosuvastatin on insulin resistance, adiposity, inflammatory markers and non-alcoholic fatty liver disease in mice fed on a high-fat diet

2012 ◽  
Vol 123 (4) ◽  
pp. 259-270 ◽  
Author(s):  
Julio Cesar Fraulob ◽  
Vanessa Souza-Mello ◽  
Marcia Barbosa Aguila ◽  
Carlos Alberto Mandarim-de-Lacerda
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
High Fat Diet ◽  
Plasma Cholesterol ◽  
Regulatory Element ◽  
Liver Steatosis ◽  
Resistance Index ◽  
Model Assessment ◽  
High Fat ◽  
Alcoholic Fatty Liver

The aim of the present study was to evaluate the effects of ST (rosuvastatin) and GZ (rosiglitazone) on IR (insulin resistance) and on liver as well as adipose tissue in mice fed on an HF (high-fat) diet. Our data show that treatment with ST resulted in a marked improvement in insulin sensitivity characterized by enhanced glucose clearance during the insulin tolerance test and a 70% decrease in the HOMA-IR (homoeostasis model assessment of insulin resistance) index level (P=0.0008). The ST-treated mice exhibited lower gains in BM (body mass; −8%; P<0.01) and visceral fat pad thickness (−60%; P<0.01) compared with the untreated HF group. In comparison with HF-diet-fed mice, HF+ST-treated mice showed a significant reduction in hepatomegaly and liver steatosis (−6%, P<0.05; and −21%, P<0.01 respectively). In HF+ST-treated mice, the hepatic TAG (triacylglycerol) levels were reduced by 58% compared with the HF group (P<0.01). In addition, the expression of SREBP-1c (sterol-regulatory-element-binding protein-1c) was decreased by 50% in the livers of HF+ST-treated mice (P<0.01) relative to the HF-diet-fed mice. The levels of resistin were lower in the HF+ST-treated group compared with the HF group (44% less, P< 0.01). In conclusion, we demonstrated that ST treatment improved insulin sensitivity and decreased liver steatosis in mice fed on an HF diet. Furthermore, ST reduced BM gains, improved the circulating levels of plasma cholesterol and TAG, and reduced hepatic TAG, which was concomitant with lower resistin levels.

scholarly journals Metformin ameliorates maternal high-fat diet-induced maternal dysbiosis and fetal liver apoptosis

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Szu-Wei Huang ◽  
Yu-Che Ou ◽  
Kuo-Shu Tang ◽  
Hong-Ren Yu ◽  
Li-Tung Huang ◽  
...  
Keyword(s):  
High Fat Diet ◽  
Fetal Liver ◽  
Liver Steatosis ◽  
Chow Diet ◽  
Obese Women ◽  
Sprague Dawley ◽  
Maternal Weight ◽  
High Fat ◽  
Alcoholic Fatty Liver ◽  
Beneficial Effects

Abstract Background The deleterious effect of maternal high-fat diet (HFD) on the fetal rat liver may cause later development of non-alcoholic fatty liver disease (NAFLD). The aim of this study was to evaluate the effect of maternal HFD-induced maternal hepatic steatosis and dysbiosis on the fetal liver and intestines, and the effect of prenatal metformin in a rat model. Methods Sprague–Dawley rats were assigned to three groups (N = 6 in each group). Before mating, the rats were randomly assigned to HFD or normal-chow diet (NCD) group for 7 weeks. After mating, the HFD group rats were continued with high-fat diet during pregnancy and some of the HFD group rats were co-treated with metformin (HFMf) via drinking water during pregnancy. All maternal rats and their fetuses were sacrificed on gestational day 21. The liver and intestinal tissues of both maternal and fetal rats were analyzed. In addition, microbial deoxyribonucleic acid extracted from the maternal fecal samples was analyzed. Results HFD resulted in maternal weight gain during pregnancy, intrahepatic lipid accumulation, and change in the serum short-chain fatty acid profile, intestinal tight junctions, and dysbiosis in maternal rats. The effect of HFD on maternal rats was alleviated by prenatal metformin, which also ameliorated inflammation and apoptosis in the fetal liver and intestines. Conclusions This study demonstrated the beneficial effects of prenatal metformin on maternal liver steatosis, focusing on the gut-liver axis. In addition, the present study indicates that prenatal metformin could ameliorate maternal HFD-induced inflammation and apoptosis in the fetal liver and intestines. This beneficial effect of in-utero exposure of metformin on fetal liver and intestines has not been reported. This study supports the use of prenatal metformin for pregnant obese women.

scholarly journals Adipose Triglyceride Lipase protects the endocytosis of renal cells on a high fat diet in Drosophila

2020 ◽  
Author(s):  
Aleksandra Lubojemska ◽  
M. Irina Stefana ◽  
Lena Lampe ◽  
Azumi Yoshimura ◽  
Alana Burrell ◽  
...  
Keyword(s):  
Lipid Droplet ◽  
High Fat Diet ◽  
Lipid Droplets ◽  
Adipose Triglyceride Lipase ◽  
Peroxisome Proliferator ◽  
Lipid Uptake ◽  
Renal Cells ◽  
High Fat ◽  
Peroxisome Proliferator Activated Receptor ◽  
Triglyceride Lipase

AbstractObesity-related renal lipotoxicity and chronic kidney disease (CKD) are prevalent pathologies with complex aetiologies. One hallmark of renal lipotoxicity is the ectopic accumulation of lipid droplets in kidney podocytes and in proximal tubule cells. Renal lipid droplets are observed in human CKD patients and in high-fat diet rodent models but their precise role remains unclear. Here, we establish a high-fat diet model in Drosophila that recapitulates renal lipid droplets and several other aspects of mammalian CKD. Cell-type specific genetic manipulations show that lipid can overflow from adipose tissue and is taken up by renal cells called nephrocytes. A high-fat diet drives nephrocyte lipid uptake via the multiligand receptor Cubilin, leading to the ectopic accumulation of lipid droplets. These nephrocyte lipid droplets correlate with ER and mitochondrial deficits, as well as with impaired macromolecular endocytosis, a key conserved function of renal cells. Nephrocyte knockdown of diglyceride acyltransferase 1 (DGAT1), overexpression of adipose triglyceride lipase (ATGL) and epistasis tests together reveal that fatty acid flux through the lipid droplet triglyceride compartment protects the ER, mitochondria and endocytosis of renal cells. Strikingly, boosting nephrocyte expression of the lipid droplet resident enzyme ATGL is sufficient to rescue high-fat diet induced defects in renal endocytosis. Moreover, endocytic rescue requires a conserved mitochondrial regulator, peroxisome proliferator-activated receptor-gamma coactivator 1α (PGC1α). This study demonstrates that lipid droplet lipolysis counteracts the harmful effects of a high-fat diet via a mitochondrial pathway that protects renal endocytosis. It also provides a genetic strategy for determining whether lipid droplets in different biological contexts function primarily to release beneficial or to sequester toxic lipids.

scholarly journals Combined Metabolic Activators Decrease Liver Steatosis by Activating Mitochondrial Metabolism in Hamsters Fed with a High-Fat Diet

Biomedicines ◽  
2021 ◽  
Vol 9 (10) ◽  
pp. 1440
Author(s):  
Hong Yang ◽  
Jordi Mayneris-Perxachs ◽  
Noemí Boqué ◽  
Josep M. del Bas ◽  
Lluís Arola ◽  
...  
Keyword(s):  
Fatty Liver ◽  
High Fat Diet ◽  
Liver Tissue ◽  
Molecular Mechanisms ◽  
De Novo ◽  
Liver Steatosis ◽  
Metabolic Model ◽  
Acid Oxidation ◽  
High Fat ◽  
Alcoholic Fatty Liver

Although the prevalence of non-alcoholic fatty liver disease (NAFLD) continues to increase, there is no effective treatment approved for this condition. We previously showed, in high-fat diet (HFD)-fed mice, that the supplementation of combined metabolic activators (CMA), including nicotinamide riboside (NAD+ precursor) and the potent glutathione precursors serine and N-acetyl-l-cysteine (NAC), significantly decreased fatty liver by promoting fat oxidation in mitochondria. Afterwards, in a one-day proof-of-concept human supplementation study, we observed that this CMA, including also L-carnitine tartrate (LCT), resulted in increased fatty acid oxidation and de novo glutathione synthesis. However, the underlying molecular mechanisms associated with supplementation of CMA have not been fully elucidated. Here, we demonstrated in hamsters that the chronic supplementation of this CMA (changing serine for betaine) at two doses significantly decreased hepatic steatosis. We further generated liver transcriptomics data and integrated these data using a liver-specific genome-scale metabolic model of liver tissue. We systemically determined the molecular changes after the supplementation of CMA and found that it activates mitochondria in the liver tissue by modulating global lipid, amino acid, antioxidant and folate metabolism. Our findings provide extra evidence about the beneficial effects of a treatment based on this CMA against NAFLD.

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.

scholarly journals The Role of Neuropeptide Y in Adipocyte-Macrophage Crosstalk during High Fat Diet-Induced Adipose Inflammation and Liver Steatosis

Biomedicines ◽  
2021 ◽  
Vol 9 (11) ◽  
pp. 1739
Author(s):  
Seongjoon Park ◽  
Toshimitsu Komatsu ◽  
Hiroko Hayashi ◽  
Ryoichi Mori ◽  
Isao Shimokawa
Keyword(s):  
Body Weight ◽  
Adipose Tissue ◽  
Neuropeptide Y ◽  
Mrna Expression ◽  
High Fat Diet ◽  
Liver Steatosis ◽  
High Fat ◽  
Alcoholic Fatty Liver ◽  
Brown Adipose ◽  
Adipose Inflammation

Obesity is associated with an increased risk of non-alcoholic fatty liver disease (NAFLD), which is initiated by adipocyte-macrophage crosstalk. Among the possible molecules regulating this crosstalk, we focused on neuropeptide Y (NPY), which is known to be involved in hypothalamic appetite and adipose tissue inflammation and metabolism. In this study, the NPY−/− mice showed a marked decrease in body weight and adiposity, and lower free fatty acid and adipose inflammation without food intake alteration during a high fat diet (HFD). Moreover, NPY deficiency increased the thermogenic genes expression in brown adipose tissue. Notably, NPY-mRNA expression was upregulated in macrophages from the HFD mice compared to that from the mice on a standard diet. The NPY-mRNA expression also positively correlated with the liver mass/body weight ratio. NPY deletion alleviated HFD-induced adipose inflammation and liver steatosis. Hence, our findings point toward a novel intracellular mechanism of NPY in the regulation of adipocyte-macrophage crosstalk and highlight NPY antagonism as a promising target for therapeutic approaches against obesity and NAFLD.

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