scholarly journals Allopurinol Prevents the Lipogenic Response Induced by an Acute Oral Fructose Challenge in Short-Term Fructose Fed Rats

Biomolecules ◽  
2019 ◽  
Vol 9 (10) ◽  
pp. 601 ◽  
Author(s):  
García-Arroyo ◽  
Monroy-Sánchez ◽  
Muñoz-Jiménez ◽  
Gonzaga ◽  
Andrés-Hernando ◽  
...  
Keyword(s):  
Uric Acid ◽  
Xanthine Oxidase ◽  
Fatty Acid Synthase ◽  
De Novo ◽  
Tap Water ◽  
De Novo Lipogenesis ◽  
Sprague Dawley ◽  
Short Term ◽  
Alcoholic Fatty Liver ◽  
High Fructose

We investigated whether short term high fructose intake may induce early hepatic dysfunction in rats and to test whether allopurinol treatment may have beneficial effects. Twenty male Sprague-Dawley rats received 20% fructose in drinking water (10 treated with allopurinol and 10 received vehicle) and 10 control rats received tap water. After 14 days, the hepatic response to an acute fructose load was evaluated, and in fasted animals, respirometry studies in freshly isolated mitochondria were performed. In fasting rats, we did not find differences in systemic or hepatic uric acid and triglyceride concentrations among the groups, but mitochondrial respiratory control rate was significantly decreased by high fructose feeding and correlated with a reduced expression of Complex I, as well as decreased aconitase-2 activity. On the other hand, in fructose fed rats, an acute fructose load increased systemic and hepatic uric acid, triglycerides and oxidative stress. Fructose feeding was also associated with fructokinase and xanthine oxidase overexpression and increased liver de novo lipogenesis program (fatty acid synthase (FAS) and cell death-inducing DFFA-like effector C (CIDEC) overexpression, ATP citrate lyase (ACL) and acetyl coA carboxylase (ACC) overactivity and decreased AMP-activated protein kinase (AMPk) and endothelial nitric oxide synthase (eNOS) activation). Allopurinol treatment prevented hepatic and systemic alterations. These data suggest that early treatment with xanthine oxidase inhibitors might provide a therapeutic advantage by delaying or even halting the progression of non-alcoholic fatty liver disease (NAFLD).

scholarly journals β-catenin mediates the effect of GLP-1 receptor agonist on ameliorating hepatic steatosis induced by high fructose diet

2020 ◽  
Vol 64 (3) ◽  
Author(s):  
Zhe Gao ◽  
Guang-Yao Song ◽  
Lu-Ping Ren ◽  
Hui-Juan Ma ◽  
Bo-Qing Ma ◽  
...  
Keyword(s):  
Hepatic Steatosis ◽  
Fatty Liver Disease ◽  
Receptor Agonist ◽  
Nuclear Translocation ◽  
De Novo ◽  
Lipid Synthesis ◽  
De Novo Lipogenesis ◽  
Alcoholic Fatty Liver ◽  
High Fructose ◽  
Alcoholic Fatty Liver Disease

The hypoglycemic drug GLP-1 receptor agonist can ameliorate hepatic steatosis but the mechanism is not clear. Intake of high fructose leads to non-alcoholic fatty liver disease by stimulating lipid synthesis, and β-catenin is the key molecule for realizing GLP-1 function in extrahepatic tissues; with the discovery of GLP-1 receptor in liver, we speculate that β-catenin might mediate GLP-1 receptor agonist on ameliorating hepatic steatosis induced by high fructose. Wistar rats were fed with high fructose diet for 8 weeks and then treated with GLP-1 receptor agonist exenatide for 4 weeks; the changes of lipid synthesis pathway factors, the expression and nuclear translocation of β-catenin, and the hepatic steatosis of the rats were observed. After the intervention of exenatide, the hepatic steatosis induced by high fructose was improved, the nuclear translocation and expression of β-catenin were facilitated, and the mRNA and protein expression of the upstream regulator SREBP-1 and the downstream key enzymes ACC, FAS and SCD-1 of de novo lipogenesis were down-regulated. GLP-1 receptor agonist may ameliorate hepatic steatosis induced by high fructose by β-catenin regulating de novo lipogenesis pathway. GLP-1 receptor agonist may be a potential new drug for the treatment of non-alcoholic fatty liver disease, and the β-catenin may be an important target for the drug therapy.

scholarly journals USP7 mediates pathological hepatic de novo lipogenesis through promoting stabilization and transcription of ZNF638

2020 ◽  
Vol 11 (10) ◽  
Author(s):  
Wenkai Ni ◽  
Shengli Lin ◽  
Saiyan Bian ◽  
Wenjie Zheng ◽  
Lishuai Qu ◽  
...  
Keyword(s):  
Fatty Acid Synthase ◽  
Zinc Finger Protein ◽  
De Novo ◽  
Binding Protein ◽  
Regulatory Element ◽  
Liver Steatosis ◽  
Underlying Mechanism ◽  
De Novo Lipogenesis ◽  
Alcoholic Fatty Liver ◽  
Element Binding Protein

Abstract Aberrant de novo lipogenesis (DNL) results in excessive hepatic lipid accumulation and liver steatosis, the causative factors of many liver diseases, such as non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and hepatocellular carcinoma (HCC). However, the underlying mechanism of DNL dysregulation remains largely unknown. Ubiquitination of proteins in hepatocytes has been shown to be widely involved in lipid metabolism of liver. Here, we revealed that Ubiquitin-specific peptidase 7 (USP7), a deubiquitinase (DUB), played key roles in DNL through regulation of zinc finger protein 638 (ZNF638) in hepatocytes. USP7 has been shown not only to interact with and deubiquitylate ZNF638, but also to facilitate the transcription of ZNF638 via the stabilization of cAMP responsive element binding protein (CREB). USP7/ZNF638 axis selectively increased the cleavage of sterol regulatory element binding protein (SREBP1C) through AKT/mTORC1/S6K signaling, and formed USP7/ZNF638/SREBP1C nuclear complex to regulate lipogenesis-associated enzymes, including acetyl-CoA carboxylase (ACACA), fatty acid synthase (FASN), and Stearoyl-CoA desaturase (SCD). In the mice liver steatosis model induced by fructose, USP7 or ZNF638 abrogation significantly ameliorated disease progression. Furthermore, USP7/ZNF638 axis participated in the progression of lipogenesis-associated HCC. Our results have uncovered a novel mechanism of hepatic DNL, which might be beneficial to the development of new therapeutic targets for hepatic lipogenesis-associated diseases.

scholarly journals Dietary Macronutrient Composition Differentially Modulates the Remodeling of Mitochondrial Oxidative Metabolism during NAFLD

Metabolites ◽  
2021 ◽  
Vol 11 (5) ◽  
pp. 272
Author(s):  
Nathan Kattapuram ◽  
Christine Zhang ◽  
Muhammed S. Muyyarikkandy ◽  
Chaitra Surugihalli ◽  
Vaishna Muralidaran ◽  
...  
Keyword(s):  
De Novo ◽  
Tca Cycle ◽  
De Novo Lipogenesis ◽  
Hepatic Insulin Resistance ◽  
Central Feature ◽  
High Fat ◽  
Alcoholic Fatty Liver ◽  
High Fructose ◽  
Gene And Protein Expression ◽  
Oxidative Function

Diets rich in fats and carbohydrates aggravate non-alcoholic fatty liver disease (NAFLD), of which mitochondrial dysfunction is a central feature. It is not clear whether a high-carbohydrate driven ‘lipogenic’ diet differentially affects mitochondrial oxidative remodeling compared to a high-fat driven ‘oxidative’ environment. We hypothesized that the high-fat driven ‘oxidative’ environment will chronically sustain mitochondrial oxidative function, hastening metabolic dysfunction during NAFLD. Mice (C57BL/6NJ) were reared on a low-fat (LF; 10% fat calories), high-fat (HF; 60% fat calories), or high-fructose/high-fat (HFr/HF; 25% fat and 34.9% fructose calories) diet for 10 weeks. De novo lipogenesis was determined by measuring the incorporation of deuterium from D2O into newly synthesized liver lipids using nuclear magnetic resonance (NMR) spectroscopy. Hepatic mitochondrial metabolism was profiled under fed and fasted states by the incubation of isolated mitochondria with [13C3]pyruvate, targeted metabolomics of tricarboxylic acid (TCA) cycle intermediates, estimates of oxidative phosphorylation (OXPHOS), and hepatic gene and protein expression. De novo lipogenesis was higher in the HFr/HF mice compared to their HF counterparts. Contrary to our expectations, hepatic oxidative function after fasting was induced in the HFr/HF group. This differential induction of mitochondrial oxidative function by the high fructose-driven ‘lipogenic’ environment could influence the progressive severity of hepatic insulin resistance.

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