scholarly journals Beneficial Effects of SREBP Decoy Oligodeoxynucleotide in an Animal Model of Hyperlipidemia

2020 ◽  
Vol 21 (2) ◽  
pp. 552 ◽  
Author(s):  
Hyun-Jin An ◽  
Jung-Yeon Kim ◽  
Mi-Gyeong Gwon ◽  
Hyemin Gu ◽  
Hyun-Ju Kim ◽  
...  
Keyword(s):  
Animal Model ◽  
Molecular Mechanisms ◽  
Metabolic Diseases ◽  
Regulatory Element ◽  
Alcoholic Fatty Liver ◽  
Health Crisis ◽  
Beneficial Effects ◽  
Lipogenic Genes ◽  
Element Binding Protein ◽  
Sterol Regulatory Element

Hyperlipidemia is a chronic disorder that plays an important role in the development of cardiovascular diseases, type II diabetes, atherosclerosis, hypertension, and non-alcoholic fatty liver disease. Hyperlipidemias have created a worldwide health crisis and impose a substantial burden not only on personal health but also on societies and economies. Transcription factors in the sterol regulatory element binding protein (SREBP) family are key regulators of the lipogenic genes in the liver. SREBPs regulate lipid homeostasis by controlling the expression of a range of enzymes required for the synthesis of endogenous cholesterol, fatty acids, triacylglycerol, and phospholipids. Thereby, SREBPs have been considered as targets for the treatment of metabolic diseases. The aim of this study was to investigate the beneficial functions and the possible underlying molecular mechanisms of SREBP decoy ODN, which is a novel inhibitor of SREBPs, in high-fat diet (HFD)-fed hyperlipidemic mice. Our studies using HFD-induced hyperlipidemia animal model revealed that SREBB decoy ODN inhibited the increased expression of fatty acid synthetic pathway, such as SREBP-1c, FAS, SCD-1, ACC1, and HMGCR. In addition, SREBP decoy ODN decreased pro-inflammatory cytokines, including TNF-α, IL-1β, IL-8, and IL-6 expression. These results suggest that SREBP decoy ODN exerts its anti-hyperlipidemia effects in HFD-induced hyperlipidemia mice by regulating their lipid metabolism and inhibiting lipogenesis through inactivation of the SREPB pathway.

scholarly journals Hepatocyte-specific Expression of Human Carboxylesterase 2 Attenuates Non-alcoholic Steatohepatitis in Mice

2020 ◽  
Author(s):  
Yanyong Xu ◽  
Xiaoli Pan ◽  
Shuwei Hu ◽  
Yingdong Zhu ◽  
Fathima Cassim Bawa ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Regulatory Element ◽  
Acid Oxidation ◽  
Specific Expression ◽  
Alcoholic Fatty Liver ◽  
Triacylglycerol Hydrolase ◽  
High Fructose ◽  
Element Binding Protein ◽  
Sterol Regulatory Element ◽  
Apoptosis And Inflammation

Human carboxylesterase 2 (CES2) has triacylglycerol hydrolase (TGH) activities and plays an important role in lipolysis. In this study, we aim to determine the role of human CES2 in the progression or reversal of steatohepatitis in diet-induced or genetically obese mice. High-fat/high-cholesterol/high-fructose (HFCF) diet-fed C57BL/6 mice or db/db mice were i.v. injected with an adeno-associated virus expressing human CES2 under the control of an albumin promoter. Human CES2 protected against HFCF diet-induced non-alcoholic fatty liver disease (NAFLD) in C57BL/6J mice and reversed steatohepatitis in db/db mice. Human CES2 also improved glucose tolerance and insulin sensitivity. Mechanistically, human CES2 reduced hepatic triglyceride and free fatty acid levels by inducing lipolysis and fatty acid oxidation and inhibiting lipogenesis via suppression of sterol regulatory element-binding protein 1. Furthermore, human CES2 overexpression improved mitochondrial respiration and glycolytic function, and inhibited gluconeogenesis, lipid peroxidation, apoptosis and inflammation. Our data suggest that hepatocyte-specific expression of human CES2 prevents and reverses steatohepatitis. Targeting hepatic CES2 may be an attractive strategy for treatment of NAFLD.

scholarly journals Estrogen Regulation of Adiposity and Fuel Partitioning

2005 ◽  
Vol 280 (43) ◽  
pp. 35983-35991 ◽  
Author(s):  
Tara M. D'Eon ◽  
Sandra C. Souza ◽  
Mark Aronovitz ◽  
Martin S. Obin ◽  
Susan K. Fried ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Free Fatty Acids ◽  
Energy Intake ◽  
Molecular Mechanisms ◽  
Ex Vivo ◽  
Regulatory Element ◽  
Estrogen Regulation ◽  
Lipogenic Genes ◽  
Element Binding Protein ◽  
Amp Activated Protein Kinase

Menopause is associated with increased adiposity and greater risk of metabolic disease. In the ovariectomized (OVX) rodent model of menopause, increased adiposity is prevented by estrogen (E2) replacement, reflecting both anorexigenic and potentially metabolic actions of E2. To elucidate metabolic and molecular mechanisms by which E2 regulates fat storage and fat mobilization independently of reduced energy intake, C57 BL/6 mice were ovariectomized, randomized to estrogen (OVX-E2) or control pellet implants (OVX-C), and pairfed for 40 days. E2 treatment was associated with reduced adipose mass and adipocyte size and down-regulation of lipogenic genes in adipocytes under the control of sterol-regulatory element-binding protein 1c. Adipocytes of OVX-E2 mice contained >3-fold more perilipin protein than adipocytes of pairfed control (OVX) mice, and this difference was associated with enhanced ex vivo lipolytic response to catecholamines and with greater levels of serum-free fatty acids following fasting. As in adipose tissue, E2 decreased the expression of lipogenic genes in liver and skeletal muscle. In the latter, E2 appears to promote the partitioning of free fatty acids toward oxidation and away from triglyceride storage by up-regulating the expression of peroxisome proliferation activator receptor-δ and its downstream targets and also by directly and rapidly activating AMP-activated protein kinase. Thus, novel genomic and non-genomic actions of E2 promote leanness in OVX mice independently of reduced energy intake.

Viral hepatitis and fatty liver disease: how an unwelcome guest makes pâté of the host

2008 ◽  
Vol 416 (2) ◽  
pp. e15-e17 ◽  
Author(s):  
Andrew J. Brown
Keyword(s):  
Liver Disease ◽  
Fatty Liver ◽  
Fatty Liver Disease ◽  
Regulatory Element ◽  
Alcoholic Fatty Liver ◽  
Biochemical Journal ◽  
Liver X Receptor Α ◽  
Element Binding Protein ◽  
Sterol Regulatory Element ◽  
Phosphoinositide 3 Kinase

HBV and HCV (hepatitis B and C viruses respectively) affect hundreds of millions of people globally, and are a major cause of chronic liver disease, including NAFLD (non-alcoholic fatty liver disease). Previous work on HCV-associated fatty liver disease has implicated two transcription factors that are important in lipid metabolism, SREBP1c (sterol-regulatory-element-binding protein 1c) and the LXRα (liver X receptor α). HBV-associated fatty liver disease has been less well-studied. New work from Kim and colleagues in this issue of the Biochemical Journal has provided new insight into how HBV causes fatty liver disease. Investigating HBV's so-called X gene product (HBx), they report that this viral protein directly binds to LXRα in the host liver cells to up-regulate the lipogenic transcription factor, SREBP1c. Also discussed in this commentary is another way that viruses such as HBV and HCV could induce SREBP1c-mediated lipogenesis, via the PI3K (phosphoinositide 3-kinase)–Akt signalling pathway.

SREBP-1c and lipogenesis in the liver: an update

2021 ◽  
Vol 478 (20) ◽  
pp. 3723-3739
Author(s):  
Pascal Ferré ◽  
Franck Phan ◽  
Fabienne Foufelle
Keyword(s):  
Endoplasmic Reticulum ◽  
Transcription Factor ◽  
Endoplasmic Reticulum Stress ◽  
Binding Protein ◽  
Regulatory Element ◽  
Activation Process ◽  
Lipogenic Genes ◽  
Regulated Intramembrane Proteolysis ◽  
Element Binding Protein ◽  
Sterol Regulatory Element

Sterol Regulatory Element Binding Protein-1c is a transcription factor that controls the synthesis of lipids from glucose in the liver, a process which is of utmost importance for the storage of energy. Discovered in the early nineties by B. Spiegelman and by M. Brown and J. Goldstein, it has generated more than 5000 studies in order to elucidate its mechanism of activation and its role in physiology and pathology. Synthetized as a precursor found in the membranes of the endoplasmic reticulum, it has to be exported to the Golgi and cleaved by a mechanism called regulated intramembrane proteolysis. We reviewed in 2002 its main characteristics, its activation process and its role in the regulation of hepatic glycolytic and lipogenic genes. We particularly emphasized that Sterol Regulatory Element Binding Protein-1c is the mediator of insulin effects on these genes. In the present review, we would like to update these informations and focus on the response to insulin and to another actor in Sterol Regulatory Element Binding Protein-1c activation, the endoplasmic reticulum stress.

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