scholarly journals The Role of the Carbohydrate Response Element-Binding Protein in Male Fructose-Fed Rats

Endocrinology ◽  
2013 ◽  
Vol 154 (1) ◽  
pp. 36-44 ◽  
Author(s):  
Derek M. Erion ◽  
Violetta Popov ◽  
Jennifer J. Hsiao ◽  
Daniel Vatner ◽  
Kisha Mitchell ◽  
...  
Keyword(s):  
De Novo ◽  
Binding Protein ◽  
De Novo Lipogenesis ◽  
Sprague Dawley ◽  
Inherited Disorders ◽  
Response Element ◽  
Nonalcoholic Fatty Liver ◽  
Hepatic Expression ◽  
Triglyceride Secretion ◽  
Element Binding Protein

By 2030, nearly half of Americans will have nonalcoholic fatty liver disease. In part, this epidemic is fueled by the increasing consumption of caloric sweeteners coupled with an innate capacity to convert sugar into fat via hepatic de novo lipogenesis. In addition to serving as substrates, monosaccharides also increase the expression of key enzymes involved in de novo lipogenesis via the carbohydrate response element-binding protein (ChREBP). To determine whether ChREBP is a potential therapeutic target, we decreased hepatic expression of ChREBP with a specific antisense oligonucleotide (ASO) in male Sprague-Dawley rats fed either a high-fructose or high-fat diet. ChREBP ASO treatment decreased plasma triglyceride concentrations compared with control ASO treatment in both diet groups. The reduction was more pronounced in the fructose-fed group and attributed to decreased hepatic expression of ACC2, FAS, SCD1, and MTTP and a decrease in the rate of hepatic triglyceride secretion. This was associated with an increase in insulin-stimulated peripheral glucose uptake, as assessed by the hyperinsulinemic-euglycemic clamp. In contrast, ChREBP ASO did not alter hepatic lipid content or hepatic insulin sensitivity. Interestingly, fructose-fed rats treated with ChREBP ASO had increased plasma uric acid, alanine transaminase, and aspartate aminotransferase concentrations. This was associated with decreased expression of fructose aldolase and fructokinase, reminiscent of inherited disorders of fructose metabolism. In summary, these studies suggest that targeting ChREBP may prevent fructose-induced hypertriglyceridemia but without the improvements in hepatic steatosis and hepatic insulin responsiveness.

scholarly journals Treatment with Ginger Ameliorates Fructose-Induced Fatty Liver and Hypertriglyceridemia in Rats: Modulation of the Hepatic Carbohydrate Response Element-Binding Protein-Mediated Pathway

2012 ◽  
Vol 2012 ◽  
pp. 1-12 ◽  
Author(s):  
Huanqing Gao ◽  
Tao Guan ◽  
Chunli Li ◽  
Guowei Zuo ◽  
Johji Yamahara ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Fatty Liver ◽  
Binding Protein ◽  
Ppar Gamma ◽  
De Novo Lipogenesis ◽  
Nonesterified Fatty Acid ◽  
Alcoholic Extract ◽  
Response Element ◽  
Hepatic Expression ◽  
Element Binding Protein

Ginger has been demonstrated to improve lipid derangements. However, its underlying triglyceride-lowering mechanisms remain unclear. Fructose overconsumption is associated with increase in hepatic de novo lipogenesis, thereby resulting in lipid derangements. Here we found that coadministration of the alcoholic extract of ginger (50 mg/kg/day, oral gavage, once daily) over 5 weeks reversed liquid fructose-induced increase in plasma triglyceride and glucose concentrations and hepatic triglyceride content in rats. Plasma nonesterified fatty acid concentration was also decreased. Attenuation of the increased vacuolization and Oil Red O staining area was evident on histological examination of liver in ginger-treated rats. However, ginger treatment did not affect chow intake and body weight. Further, ginger treatment suppressed fructose-stimulated overexpression of carbohydrate response element-binding protein (ChREBP) at the mRNA and protein levels in the liver. Consequently, hepatic expression of the ChREBP-targeted lipogenic genes responsible for fatty acid biosynthesis was also downregulated. In contrast, expression of neither peroxisome proliferator-activated receptor- (PPAR-) alpha and its downstream genes, nor PPAR-gamma and sterol regulatory element-binding protein 1c was altered. Thus the present findings suggest that in rats, amelioration of fructose-induced fatty liver and hypertriglyceridemia by ginger treatment involves modulation of the hepatic ChREBP-mediated pathway.

scholarly journals Paradoxical Dissociation Between Hepatic Fat Content and De Novo Lipogenesis Due to PNPLA3 Sequence Variant

2015 ◽  
Vol 100 (5) ◽  
pp. E821-E825 ◽  
Author(s):  
Rosellina M. Mancina ◽  
Niina Matikainen ◽  
Cristina Maglio ◽  
Sanni Söderlund ◽  
Nina Lundbom ◽  
...  
Keyword(s):  
De Novo ◽  
Fat Content ◽  
De Novo Lipogenesis ◽  
Liver Fat ◽  
Sequence Variant ◽  
Deuterated Water ◽  
Epidemic Disease ◽  
Nonalcoholic Fatty Liver ◽  
Hepatic Expression ◽  
Hepatic Fat

Abstract Context: Nonalcoholic fatty liver disease (NAFLD) is an emerging epidemic disease characterized by increased hepatic fat, due to an imbalance between synthesis and removal of hepatic lipids. In particular, increased hepatic de novo lipogenesis (DNL) is a key feature associated with NAFLD. The genetic variations I148M in PNPLA3 and E167K in TM6SF2 confer susceptibility to NAFLD. Objective: Here we aimed to investigate the contribution of DNL to liver fat accumulation in the PNPLA3 I148M or TM6SF2 E167K genetic determinants of NAFLD. Patients and Methods: The PNPLA3 I148M and TM6SF2 E167K were genotyped in two well-characterized cohorts of Europeans. In the first cohort (Helsinki cohort; n = 88), we directly quantified hepatic DNL using deuterated water. In the second cohort (Milan cohort; n = 63), we quantified the hepatic expression of SREBP1c that we have found previously associated with increased fat content. Liver fat was measured by magnetic resonance proton spectroscopy in the Helsinki cohort, and by histological assessment of liver biopsies in the Milan cohort. Results: PNPLA3 148M was associated with lower DNL and expression of the lipogenic transcription factor SREBP1c despite substantial increased hepatic fat content. Conclusions: Our data show a paradoxical dissociation between hepatic DNL and hepatic fat content due to the PNPLA3 148M allele indicating that increased DNL is not a key feature in all individuals with hepatic steatosis, and reinforces the contribution of decreased mobilization of hepatic triglycerides for hepatic lipid accumulation in subject with the PNPLA3 148M allele.

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 The role of the glucose-sensing transcription factor carbohydrate-responsive element-binding protein pathway in termite queen fertility

Open Biology ◽  
2016 ◽  
Vol 6 (5) ◽  
pp. 160080 ◽  
Author(s):  
David Sillam-Dussès ◽  
Robert Hanus ◽  
Michael Poulsen ◽  
Virginie Roy ◽  
Maryline Favier ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Fatty Acid Synthase ◽  
De Novo ◽  
Binding Protein ◽  
Glucose Sensing ◽  
De Novo Lipogenesis ◽  
Organic Polymer ◽  
Key Factor ◽  
Element Binding Protein ◽  
Responsive Element

Termites are among the few animals that themselves can digest the most abundant organic polymer, cellulose, into glucose. In mice and Drosophila , glucose can activate genes via the transcription factor carbohydrate-responsive element-binding protein (ChREBP) to induce glucose utilization and de novo lipogenesis. Here, we identify a termite orthologue of ChREBP and its downstream lipogenic targets, including acetyl-CoA carboxylase and fatty acid synthase. We show that all of these genes, including ChREBP, are upregulated in mature queens compared with kings, sterile workers and soldiers in eight different termite species. ChREBP is expressed in several tissues, including ovaries and fat bodies, and increases in expression in totipotent workers during their differentiation into neotenic mature queens. We further show that ChREBP is regulated by a carbohydrate diet in termite queens. Suppression of the lipogenic pathway by a pharmacological agent in queens elicits the same behavioural alterations in sterile workers as observed in queenless colonies, supporting that the ChREBP pathway partakes in the biosynthesis of semiochemicals that convey the signal of the presence of a fertile queen. Our results highlight ChREBP as a likely key factor for the regulation and signalling of queen fertility.

scholarly journals Correction to: The role of hepatic transcription factor cAMP response element-binding protein (CREB) during the development of experimental nonalcoholic fatty liver: a biochemical and histomorphometric study

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Ashraf K. Awaad ◽  
Maher A. Kamel ◽  
Magdy M. Mohamed ◽  
Madiha H. Helmy ◽  
Magda I. Youssef ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Fatty Liver ◽  
Binding Protein ◽  
Camp Response Element Binding ◽  
Camp Response Element ◽  
Response Element ◽  
Nonalcoholic Fatty Liver ◽  
Histomorphometric Study ◽  
Element Binding Protein

An amendment to this paper has been published and can be accessed via the original article.

scholarly journals The role of hepatic transcription factor cAMP response element-binding protein (CREB) during the development of experimental nonalcoholic fatty liver: a biochemical and histomorphometric study

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Ashraf K. Awaad ◽  
Maher A. Kamel ◽  
Magdy M. Mohamed ◽  
Madiha H. Helmy ◽  
Magda I. Youssef ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Fatty Liver ◽  
Binding Protein ◽  
Camp Response Element Binding ◽  
Control Group ◽  
Camp Response Element ◽  
Response Element ◽  
Nonalcoholic Fatty Liver ◽  
Element Binding Protein

Abstract Background Several molecular mechanisms contribute to the initiation and progression of nonalcoholic fatty liver disease (NAFLD); however, the exact mechanism is not completely understood. Cyclic adenosine monophosphate (cAMP) is one of the most promising pathways that regulates various cellular functions including lipid and carbohydrate metabolism. cAMP induces gene transcription through phosphorylation of the transcription factor, cAMP response element-binding protein (CREB). The action of cAMP is tightly regulated by its level and repression. Among the repressors, Inducible cAMP Early Repressor (ICER) is the only inducible CRE-binding protein. The present study aimed to evaluate the role of hepatic CREB level in the development of experimental NAFLD model to clarify the pathogenesis of the disease. NAFLD 35 male Wistar rats fed a high fat diet for a period of 14 weeks were studied compared with 35 control rats fed a standard diet. Five fasting rats were sacrificed each 2 weeks intervals for a period of 14 weeks. Results NAFLD group revealed a remarkable duration—dependent elevation in cAMP and CREB levels in the liver tissue compared to control group (P value < 0.004, P value < 0.006, respectively). In contrast, ICER gene expression, as a dominant-negative regulator of CREB, was downregulated in the liver of NAFLD group compared to control group. We also demonstrated that CREB levels were positively correlated with liver function tests, and glucose homeostasis parameters. Conclusions Our results indicate that cAMP/CREB pathway provides an early signal in the progression to NAFLD representing a noninvasive biomarker that can early detect NAFLD and a promising therapeutic target for the treatment of the disease as well.

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