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 Diphlorethohydroxycarmalol Attenuates Palmitate-Induced Hepatic Lipogenesis and Inflammation

Marine Drugs ◽  
2020 ◽  
Vol 18 (9) ◽  
pp. 475
Author(s):  
Seon-Heui Cha ◽  
Yongha Hwang ◽  
Soo-Jin Heo ◽  
Hee-Sook Jun
Keyword(s):  
Liver Disease ◽  
Fatty Liver ◽  
Fatty Acid Synthase ◽  
Metabolic Diseases ◽  
Binding Protein ◽  
Regulatory Element ◽  
Protective Effects ◽  
Alcoholic Fatty Liver ◽  
Edible Seaweed ◽  
Element Binding Protein

Non-alcoholic fatty liver disease (NAFLD) is a common cause of chronic liver disease, encompassing a range of conditions caused by lipid deposition within liver cells, and is also associated with obesity and metabolic diseases. Here, we investigated the protective effects of diphlorethohydroxycarmalol (DPHC), which is a polyphenol isolated from an edible seaweed, Ishige okamurae, on palmitate-induced lipotoxicity in the liver. DPHC treatment repressed palmitate-induced cytotoxicity, triglyceride content, and lipid accumulation. DPHC prevented palmitate-induced mRNA and protein expression of SREBP (sterol regulatory element-binding protein) 1, C/EBP (CCAAT-enhancer-binding protein) α, ChREBP (carbohydrate-responsive element-binding protein), and FAS (fatty acid synthase). In addition, palmitate treatment reduced the expression levels of phosphorylated AMP-activated protein kinase (AMPK) and sirtuin (SIRT)1 proteins, and DPHC treatment rescued this reduction. Moreover, DPHC protected palmitate-induced liver toxicity and lipogenesis, as well as inflammation, and enhanced AMPK and SIRT1 signaling in zebrafish. These results suggest that DPHC possesses protective effects against palmitate-induced toxicity in the liver by preventing lipogenesis and inflammation. DPHC could be used as a potential therapeutic or preventive agent for fatty liver diseases.

Regulation of fatty acid synthase expression in breast cancer by sterol regulatory element binding protein-1c

2003 ◽  
Vol 282 (2) ◽  
pp. 132-137 ◽  
Author(s):  
Y.u-A.n Yang ◽  
Patrice J. Morin ◽  
Wan Fang Han ◽  
Tinghua Chen ◽  
Daniel M. Bornman ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Fatty Acid ◽  
Fatty Acid Synthase ◽  
Binding Protein ◽  
Regulatory Element ◽  
Element Binding Protein ◽  
Sterol Regulatory Element

Regulation of the SREBP transcription factors by mTORC1

2011 ◽  
Vol 39 (2) ◽  
pp. 495-499 ◽  
Author(s):  
Caroline A. Lewis ◽  
Beatrice Griffiths ◽  
Claudio R. Santos ◽  
Mario Pende ◽  
Almut Schulze
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Synthase ◽  
Target Genes ◽  
De Novo ◽  
Regulatory Element ◽  
Cholesterol Biosynthesis ◽  
Mammalian Target Of Rapamycin ◽  
Lipid Biosynthesis ◽  
De Novo Lipogenesis ◽  
Genes Encoding

In recent years several reports have linked mTORC1 (mammalian target of rapamycin complex 1) to lipogenesis via the SREBPs (sterol-regulatory-element-binding proteins). SREBPs regulate the expression of genes encoding enzymes required for fatty acid and cholesterol biosynthesis. Lipid metabolism is perturbed in some diseases and SREBP target genes, such as FASN (fatty acid synthase), have been shown to be up-regulated in some cancers. We have previously shown that mTORC1 plays a role in SREBP activation and Akt/PKB (protein kinase B)-dependent de novo lipogenesis. Our findings suggest that mTORC1 plays a crucial role in the activation of SREBP and that the activation of lipid biosynthesis through the induction of SREBP could be part of a regulatory pathway that co-ordinates protein and lipid biosynthesis during cell growth. In the present paper, we discuss the increasing amount of data supporting the potential mechanisms of mTORC1-dependent activation of SREBP as well as the implications of this signalling pathway in cancer.

Abstract 325: Response Gene to Complement 32 Deficiency Protects Against Hepatic Steatosis by Inhibiting Lipogenesis in Mice

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Xiaobing Cui ◽  
Junna Luan ◽  
Shiyou Chen
Keyword(s):  
Hepatic Steatosis ◽  
Fatty Acid Synthase ◽  
De Novo ◽  
Regulatory Element ◽  
In Vitro Study ◽  
De Novo Lipogenesis ◽  
Dependent Manner ◽  
Response Gene ◽  
Normal Chow

Hepatic steatosis is associated with obesity due to the increased lipogenesis. Previously, we have found that RGC-32 (response gene to complement 32) deficiency prevents the mice from high-fat diet (HFD)-induced obesity and insulin resistance. The present study was conducted to determine the role of RGC-32 in the control of hepatic steatosis. We observed that hepatic RGC-32 expression was dramatically induced by HFD challenge. RGC-32 knockout (RGC32-/-) mice were resistant to HFD-induced hepatic steatosis. More importantly, hepatic triglyceride contents of RGC32-/- mice were significantly decreased compared with wild-type (WT) controls on both normal chow and HFD. Mechanistically, RGC-32 deficiency decreased expression of lipogenesis-related genes, sterol regulatory element (SRE) binding protein (SREBP)-1c, fatty acid synthase (FAS) and stearoyl-CoA desaturase-1 (SCD1). Our in vitro study showed that RGC-32 knockdown decreased while RGC-32 overexpression increased SCD1 expression in hepatocytes. Deletion or mutation of SRE in the SCD1 promoter abolished the function of RGC-32. These data demonstrate that RGC-32 contributes to HFD-induced hepatic steatosis by facilitating de novo lipogenesis in a SREBP-1c dependent manner. Therefore, RGC-32 may be a novel drug target in the treatment of hepatic steatosis and its related diseases.

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