Abstract 574: Whole Body and Hepatocyte-specific Deletion of Bmal1 Induces Hyperlipidemia and Enhances Atherosclerosis

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Xiaoyue Pan ◽  
Mahmood M Hussain
Keyword(s):  
Plasma Lipids ◽  
Microsomal Triglyceride Transfer Protein ◽  
Diurnal Rhythms ◽  
Whole Body ◽  
Over Expression ◽  
Transfer Protein ◽  
High Incidence ◽  
Clock Mutant ◽  
Accumulation Of Lipids ◽  
Specific Deletion

The aberrant accumulation of lipids in the plasma is associated with high incidence of atherosclerosis. Plasma lipids exhibit diurnal variations. Diurnal rhythms are controlled by two major transcription factors, Clock and Bmal1. Previously, we have shown that expression of a Clock mutant protein predisposes mice to hyperlipidemia and atherosclerosis. Here we show that the complete and liver-specific ablation of Bmal1 gene expression in Apoe -/- mice promotes hyperlipidemia and atherosclerosis. We observed that Bmal1 deficiency increases of microsomal triglyceride transfer protein (MTP) expression. Molecular studies indicated that Bmal1 deficiency decreases the expression of small heterodimer partner (SHP), a repressor MTP, to increase MTP expression and hepatic lipoprotein production. The effect of Bmal1 deficiency on MTP can be circumvented by the hepatic over expression of SHP. Over expression of SHP in the liver-specific Bmal1 deficient Apoe -/- mice reduced atherosclerosis and plasma lipids. These studies show that Bmal1 regulates hepatic lipoprotein production by regulating SHP. Deregulation of these circadian regulatory mechanisms and physiologic pathways predisposes mice to hyperlipidemia and atherosclerosis.

Abstract 115: Microrna-30c Reduces Hyperlipidemia and Atherosclerosis by Decreasing Lipid Synthesis and Lipoprotein Secretion

2013 ◽  
Vol 33 (suppl_1) ◽  
Author(s):  
James Soh ◽  
Jahangir Iqbal ◽  
Joyce Queiroz ◽  
Carlos Fernandez-Hernando ◽  
M. Mahmood Hussain
Keyword(s):  
Metabolic Disorders ◽  
Plasma Lipids ◽  
De Novo ◽  
Plasma Cholesterol ◽  
Lipid Synthesis ◽  
Microsomal Triglyceride Transfer Protein ◽  
Atherosclerotic Plaques ◽  
Over Expression ◽  
Transfer Protein ◽  
Lipoprotein Secretion

Hyperlipidemia is a risk factor for various cardiovascular and metabolic disorders. Overproduction of lipoproteins, a process critically dependent on microsomal triglyceride transfer protein (MTP), can contribute to hyperlipidemia. We have shown that hepatic over expression of miR-30c reduces MTP mRNA, protein and activity. Further, MTP mRNA is degraded faster due to the binding of miR-30c to its 3[[Unable to Display Character: ΄]]-UTR. miR-30c lowers plasma cholesterol by reducing production of triglyceride-rich apoB-containing lipoproteins; a phenotype most likely secondary to lower MTP expression. It also reduces de novo lipogenesis by targeting other genes such as LPGAT1. Additionally, atherosclerotic plaques are smaller in Apoe -/- mice expressing miR-30c. Taken together, we have provided evidence that high miR-30c levels reduce plasma lipids and atherosclerosis and avoids steatosis by regulating different sets of genes.

scholarly journals Microsomal Triglyceride Transfer Protein Inhibition Induces Endoplasmic Reticulum Stress and Increases Gene Transcription via Ire1α/cJun to Enhance Plasma ALT/AST

2013 ◽  
Vol 288 (20) ◽  
pp. 14372-14383 ◽  
Author(s):  
Joby Josekutty ◽  
Jahangir Iqbal ◽  
Takao Iwawaki ◽  
Kenji Kohno ◽  
M. Mahmood Hussain
Keyword(s):  
Endoplasmic Reticulum ◽  
Free Cholesterol ◽  
Plasma Lipids ◽  
Microsomal Triglyceride Transfer Protein ◽  
Major Mechanism ◽  
Protein Inhibition ◽  
Transfer Protein ◽  
Oxidative Stresses ◽  
Triglyceride Rich Lipoprotein ◽  
Response To Stress

Microsomal triglyceride transfer protein (MTP) is a target to reduce plasma lipids because of its indispensable role in triglyceride-rich lipoprotein biosynthesis. MTP inhibition in Western diet fed mice decreased plasma triglycerides/cholesterol, whereas increasing plasma alanine/aspartate aminotransferases (ALT/AST) and hepatic triglycerides/free cholesterol. Free cholesterol accumulated in the endoplasmic reticulum (ER) and mitochondria resulting in ER and oxidative stresses. Mechanistic studies revealed that MTP inhibition increased transcription of the GPT/GOT1 genes through up-regulation of the IRE1α/cJun pathway leading to increased synthesis and release of ALT1/AST1. Thus, transcriptional up-regulation of GPT/GOT1 genes is a major mechanism, in response to ER stress, elevating plasma transaminases. Increases in plasma and tissue transaminases might represent a normal response to stress for survival.

scholarly journals Intestine-Specific Deletion of Microsomal Triglyceride Transfer Protein Increases Mortality in Aged Mice

PLoS ONE ◽  
2014 ◽  
Vol 9 (7) ◽  
pp. e101828 ◽  
Author(s):  
Zhe Liang ◽  
Yan Xie ◽  
Jessica A. Dominguez ◽  
Elise R. Breed ◽  
Benyam P. Yoseph ◽  
...  
Keyword(s):  
Microsomal Triglyceride Transfer Protein ◽  
Aged Mice ◽  
Transfer Protein ◽  
Specific Deletion

Roles of phosphatidylinositol 3-kinase and osteopontin in steatosis and aminotransferase release by hepatocytes treated with methionine-choline-deficient medium

2006 ◽  
Vol 291 (1) ◽  
pp. G55-G62 ◽  
Author(s):  
Atul Sahai ◽  
Xiaomin Pan ◽  
Rachelle Paul ◽  
Padmini Malladi ◽  
Rohit Kohli ◽  
...  
Keyword(s):  
Animal Model ◽  
Culture Medium ◽  
Microsomal Triglyceride Transfer Protein ◽  
Pi3 Kinase ◽  
Cultured Hepatocytes ◽  
Phosphatidylinositol 3 Kinase ◽  
Over Expression ◽  
Downstream Target ◽  
Transfer Protein ◽  
Deficient Medium

Feeding mice a methionine and choline-deficient (MCD) diet serves as an experimental animal model for nonalcoholic steatohepatitis (NASH). In the present study we examined the effect of exposing AML-12 hepatocytes to MCD culture medium in regard to mechanisms of steatosis and alanine amino-transferase (ALT) release. Cells exposed to MCD medium developed significant and progressive steatosis from 6 to 24 h and also had significantly increased loss of ALT into the medium at 18 and 24 hours of incubation. No increased oxidative injury or cell death was observed. Osteopontin (OPN) mRNA in cells and protein expression in medium were significantly increased during 6–24 hours of incubation. MCD medium treatment also resulted in activation of PI3-kinase by 30 minutes and its downstream target p-Akt within 1hour of incubation. Steatosis was associated with increased expression of microsomal triglyceride transfer protein (MTTP) mRNA and increased ALT release with over expression of ALT mRNA, all of which were completely prevented by inhibition of PI3-kinase (LY294002). Blocking OPN signaling by treating with anti-OPN or anti-β3-integrin antibody prevented the increased ALT release while only partially prevented the increased ALT mRNA expression, but had no effect on either steatosis or MTTP expression. In conclusion, incubation of cultured hepatocytes with MCD medium results in cellular steatosis and OPN dependent ALT release. PI3-kinase plays a central role in signaling the MCD medium-induced steatosis and increased OPN expression, whereas OPN appears to play a role in signaling hepatocyte ALT release but not steatosis.

Abstract 399: Increased Gene Transcription via Ire1a/cJun Enhances Plasma ALT/AST in MTP Inhibited and MCD Diet Fed Mice

2013 ◽  
Vol 33 (suppl_1) ◽  
Author(s):  
Joby Josekutty ◽  
Jahangir Iqbal ◽  
Takao Iwawaki ◽  
Kenji Kohno ◽  
M. Mahmood Hussain
Keyword(s):  
Free Cholesterol ◽  
Plasma Lipids ◽  
Microsomal Triglyceride Transfer Protein ◽  
Mechanistic Studies ◽  
Deficient Diet ◽  
Plasma Triglycerides ◽  
Major Mechanism ◽  
Transfer Protein ◽  
Oxidative Stresses ◽  
Triglyceride Rich Lipoprotein

Microsomal triglyceride transfer protein (MTP) is a target to reduce plasma lipids because of its indispensable role in triglyceride-rich lipoprotein biosynthesis. MTP inhibition in western diet fed mice decreased plasma triglycerides/cholesterol while increasing plasma alanine/aspartate aminotransferases (ALT/AST) and hepatic triglycerides/free cholesterol. Free cholesterol accumulated in the endoplasmic reticulum (ER) and mitochondria resulting in ER and oxidative stresses. Mechanistic studies revealed that MTP inhibition increased transcription of the GPT/GOT1 genes through up-regulation of the IRE1α/cJun pathway leading to increased synthesis and release of ALT1/AST1. We also observed that IRE1α/cJun pathway is involved in augmenting plasma ALT/AST in mice fed methionine-choline deficient diet. Thus, transcriptional up-regulation of GPT/GOT1 genes is a major mechanism elevating plasma transaminases under different conditions.

Abstract 426: MicroRNA-30c Mimic Treatment Attenuates Hypercholesterolemia and Atherosclerosis in Mice

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Sara Irani ◽  
Xiaoyue Pan ◽  
Bailey Peck ◽  
Jahangir Iqbal ◽  
Praveen Sethupathy ◽  
...  
Keyword(s):  
Plasma Cholesterol ◽  
Lipid Synthesis ◽  
Microsomal Triglyceride Transfer Protein ◽  
Bioinformatic Analysis ◽  
High Plasma ◽  
Over Expression ◽  
Hepatic Lipids ◽  
Transfer Protein ◽  
Cholesterol Levels ◽  
Viral Therapy

Background: High plasma cholesterol levels are a major risk factor for atherosclerosis. Plasma cholesterol can be reduced by inhibiting lipoprotein production; however, this is associated with steatosis. Previously we showed that lentiviral mediated hepatic over-expression of microRNA-30c (miR-30c) reduced hyperlipidemia and atherosclerosis in mice without causing hepatosteatosis. Since viral therapy would be formidable, we tested the hypothesis that a miR-30c oligonucleotide mimic can mitigate hyperlipidemia and atherosclerosis without causing steatosis. Methods and results: Delivery of a miR-30c mimic to the liver diminished Western diet-induced hypercholesterolemia in C57BL/6J wild type mice. Reductions in plasma cholesterol levels were significantly correlated with increases in hepatic miR-30c levels. Long-term dose escalation studies showed that miR-30c mimic causes sustained reductions in plasma cholesterol without increasing hepatic lipids and plasma transaminases. Further, miR-30c mimic significantly reduced hypercholesterolemia and atherosclerosis in Apoe –/– mice without causing steatosis or increasing plasma transaminases. Mechanistic studies indicated that miR-30c mimic reduced hepatic lipoprotein production, in part by reducing microsomal triglyceride transfer protein (MTP) activity. This is supported by the observation that miR-30c did not lower plasma cholesterol in liver-specific MTP deficient mice but did reduce hepatic lipid synthesis. In order to understand why there was no increase in hepatic lipids, we carried out whole transcriptome studies by RNA-sequencing. Bioinformatic analysis of the data revealed that genes down-regulated by miR-30c mimic are most significantly enriched for lipid synthesis pathways. Consistent with this finding, we showed that miR-30c mimic reduced fatty acid and glycerolipid synthesis in the liver but had no effect on hepatic β-oxidation. Conclusions: We conclude that miR-30c reduces plasma cholesterol by targeting MTP and prevents hepatosteatosis by repressing lipid synthesis programs in the liver. These findings suggest that increasing hepatic miR-30c levels may be a viable treatment modality for hypercholesterolemia and atherosclerosis.

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