Altered hepatic lipid metabolism in C57BL/6 mice fed alcohol: a targeted lipidomic and gene expression study

Clugston, Robin D.; Jiang, Hongfeng; Lee, Man Xia; Piantedosi, Roseann; Yuen, Jason J.; Ramakrishnan, Rajasekhar; Lewis, Michael J.; Gottesman, Max E.; Huang, Li‐Shin; Goldberg, Ira J.; Berk, Paul D.; Blaner, William S.

doi:10.1194/jlr.m017368

Cited by 91 publications

(127 citation statements)

References 58 publications

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“…Approximately 60% of the FA in the diet used for these studies consisted of monounsaturated FA. Substantial differences in PUFAs (C18:2, C20:4) were observed in FFA, TG, PL, and microsomal lipids in WT ethanol mice, supporting recent reports from Clugston et al ( 6 ). These data suggest that, in mice, FAs are oxidized, newly synthesized, and/or imported from the adipose tissue.…”

Section: Ethanol Ingestion Alters Transcription Factor Activitysupporting

confidence: 77%

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Susceptibility of L-FABP−/− mice to oxidative stress in early-stage alcoholic liver

Smathers

Galligan

Shearn

et al. 2013

Journal of Lipid Research

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As chronic alcohol consumption continues to be a socioeconomic burden in the United States, a growing need to further understand hepatic disease progression and to develop therapeutic intervention for dependents is rising. Recent reports have identifi ed alcoholic liver disease (ALD) as the third leading preventable cause of death, accounting for nearly 13,000 deaths in 2006 ( 1, 2 ). It has been hypothesized that early-stage ALD, namely steatosis or fatty liver, occurs as a result of the dysregulation of fatty acids (FA) through synthesis and oxidation, storage, and/ or import/export mechanisms ( 3 ). Following sustained ethanol consumption, progressive stages of ALD, including hepatitis and cirrhosis, will occur in roughly 10-15% of the US population ( 4 ).The oxidative metabolism of ethanol is known to induce hepatic stress. Coupled with the generation of reactive oxygen species (ROS), lipid peroxidation (LPO) and infl ammation often parallel early-stage pathogenesis. Consumption of ethanol also alters metabolic pathways that modulate FA homeostasis in the liver ( 5 ). Recent reports have identifi ed alterations in FA traffi cking and lipid peroxidation as critical targets for modulation in the setting

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Section: Ethanol Ingestion Alters Transcription Factor Activitysupporting

confidence: 77%

“…Briefl y, 100 µg of PPAR ␣ ab (Thermo, cat# of alcoholic liver injury (6)(7)(8). Liver fatty acid-binding protein (L-FABP) is highly expressed in the cytosol of hepatocytes and exhibits high affi nities for lipid ligands (capable of binding two simultaneously) in the high nanomolar to low micromolar range.…”

Section: Coimmunoprecipitation Of Protein Complexesmentioning

confidence: 99%

Susceptibility of L-FABP−/− mice to oxidative stress in early-stage alcoholic liver

Smathers

Galligan

Shearn

et al. 2013

Journal of Lipid Research

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“…Optimized cone voltage was 16 V, collision energy for multiple reaction monitoring mode (MRM) was 18 eV, and the following transitions were used: atRA for quantifi cation, m/z 301. 16 The extraction and LC/MS/MS protocols employed for the analysis of hepatic endocannabinoids employing a MRM methodology have been described in detail elsewhere ( 28 ).…”

Section: Animal Husbandry and Dietary Regimensmentioning

confidence: 99%

Hepatic retinoid stores are required for normal liver regeneration

Shmarakov

Jiang

Yang

et al. 2013

Journal of Lipid Research

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“…Lipid analyses by LC/MS were performed as recently reported ( 21 ). Briefl y, all solutions and solvents used for lipid extraction were precooled at 4°C.…”

Section: Lc/msmentioning

confidence: 99%

“…[ 3 H]triolein bands from the same TLC plates were identifi ed and quantifi ed in the same way and were used as controls for lipid recovery. LC/MS analyses were performed as described previously ( 21 ).…”

mentioning

confidence: 99%

Diacylglycerol acyl transferase 1 overexpression detoxifies cardiac lipids in PPARγ transgenic mice

Liu刘立

Khan

et al. 2012

Journal of Lipid Research

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This article is available online at http://www.jlr.org create a group of diseases classifi ed as lipotoxicities. These diseases include nonalcoholic fatty liver disease, type 2 diabetes, and metabolic cardiomyopathy ( 2 ).The major storage form of lipids within the body is triglyceride (TG), a lipid that is believed to be biologically inert ( 3 ). Diacylglycerol (DAG) acyl transferase 1 (DGAT1) is one of two enzymes that catalyze the fi nal step in TG synthesis. Dgat1 belongs to a gene family that includes acylCoA:cholesterol acyltransferases 1 and 2 ( 4 ). DGAT1 has been overexpressed in mice to elucidate the function of this gene in the development of metabolic disease. In skeletal muscle, overexpression of DGAT1 increased TG stores but reduced DAG and ceramide, increased FA oxidation, and improved insulin sensitivity ( 5 ); this mimics the biology of chronic exercise and is sometimes referred to as the "athlete paradox" ( 6, 7 ). Overexpression of DGAT1 in adipose tissue using an AP2 promoter led to greater obesity but not insulin resistance in C57BL6 mice ( 8 ). FVB mice, however, still had insulin resistance ( 9 ), a fi nding that might refl ect genotype differences or variation in macrophage DGAT1 expression with the AP2 promoter. Overexpression of DGAT1 in the liver ( 10 ) and heart ( 11 ) increased TG content of those tissues but did not cause insulin resistance or heart dysfunction. Similarly, overexpression of DGAT1 in macrophages ameliorated FA-induced infl ammation and high-fat feeding-induced insulin resistance ( 12 ). These data support the hypothesis that conversion of intermediary toxic lipids to TG via DGAT1 can be a detoxifying process ( 3 ).Lipotoxic cardiomyopathy models have been created in which lipid oxidation is insufficient to balance lipid uptake, leading to increased accumulation of TG, free FA Abstract Accumulation of excess lipids is associated with heart failure. The effects of transgenic expression of diacylglycerol acyl transferase 1 (DGAT1) in cardiomyocytes is controversial. We explored whether mice expressing DGAT1 via the myosin heavy chain (MHC) promoter develop heart dysfunction with aging or after crossing with mice overexpressing peroxisome proliferator-activated receptor ␥ (PPAR ␥ ) in the heart. MHC-DGAT1 transgenic mice had increased heart triglyceride but no evidence of heart dysfunction, even up to age 12 months. The MHC-DGAT1 transgene improved heart dysfunction and survival of MHC-PPAR ␥ -expressing transgenic mice. Both diacylglycerol and ceramide levels in the heart were reduced by this cross, as were the levels of several mRNAs of genes involved in lipid metabolism. There were fewer large lipid droplets in MHC-DGAT1×MHC-PPAR ␥ mice compared with MHC-PPAR ␥ , but total lipid content was not changed. Therefore, overexpression of DGAT1 is not toxic to the heart but reduces levels of toxic lipids and improves lipotoxic cardiomyopathy. Moreover, the benefi cial effects of DGAT1 illustrate the interrelationship of several lipid metabolic pathways and the diffi culty of...

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Altered hepatic lipid metabolism in C57BL/6 mice fed alcohol: a targeted lipidomic and gene expression study

Cited by 91 publications

References 58 publications

Susceptibility of L-FABP−/− mice to oxidative stress in early-stage alcoholic liver

Susceptibility of L-FABP−/− mice to oxidative stress in early-stage alcoholic liver

Hepatic retinoid stores are required for normal liver regeneration

Diacylglycerol acyl transferase 1 overexpression detoxifies cardiac lipids in PPARγ transgenic mice

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