Hepatic deletion of Mboat7 (LPIAT1) causes activation of SREBP-1c and fatty liver

Xia, Mingfeng; Chandrasekaran, Preethi; Rong, Shunxing; Fu, Xiaorong; Mitsche, Matthew A.

doi:10.1194/jlr.ra120000856

Cited by 48 publications

(92 citation statements)

References 49 publications

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“…The resultant impairment in LPI metabolism led to a reduction of AA-containing PI and accumulation of saturated LPI, that are next converted to TAG synthesis by the alternative pathway through diacylglycerol (DAG), contributing to LD formation (Figure 3) [68,90]. This process is associated with upregulation of lipogenesis with SREBP-1c [68,93]. Moreover, the deficiency of AAcontaining PI upregulated CDP-diacylglycerol (CDP-DAG) synthase (CDS), causing accelerated PI synthesis, and promoted PI degradation into DAG through the phospholipase C (PLC), triggering a vicious cycle that generates TAG leading to steatosis [90].…”

Section: From Quantitative To Qualitative Alterations Of Liver Fat: Tmentioning

confidence: 99%

Genetic predisposition similarities between NASH and ASH: Identification of new therapeutic targets

et al. 2021

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This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Section: From Quantitative To Qualitative Alterations Of Liver Fat: Tmentioning

confidence: 99%

Genetic predisposition similarities between NASH and ASH: Identification of new therapeutic targets

et al. 2021

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“…Indeed, a derangement in MBOAT7 function contributes to accumulate saturated phospholipids, mainly, PI species that may be shunted to saturated and mono-unsaturated TG synthesis, further sustaining fatty-laden hepatocyte formation [109,132]. In line with this data, MBOAT7 breakage hustles the induction of lipogenic program, due to ER stress and to the activation of SREBP-1c, a transcription factor that coordinates the activation of genes involved in fatty acid biosynthesis [135]. The causative role of MBOAT7 in fatty liver has been independently reported by Helsley [133] and then by Tanaka [136].…”

Section: Mboat7: a Common Modifier Of Liver Damagementioning

confidence: 61%

Genetics Is of the Essence to Face NAFLD

et al. 2021

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Nonalcoholic fatty liver disease (NAFLD) is the commonest cause of chronic liver disease worldwide. It is closely related to obesity, insulin resistance (IR) and dyslipidemia so much so it is considered the hepatic manifestation of the Metabolic Syndrome. The NAFLD spectrum extends from simple steatosis to nonalcoholic steatohepatitis (NASH), a clinical condition which may progress up to fibrosis, cirrhosis and hepatocellular carcinoma (HCC). NAFLD is a complex disease whose pathogenesis is shaped by both environmental and genetic factors. In the last two decades, several heritable modifications in genes influencing hepatic lipid remodeling, and mitochondrial oxidative status have been emerged as predictors of progressive hepatic damage. Among them, the patatin-like phospholipase domain-containing 3 (PNPLA3) p.I148M, the Transmembrane 6 superfamily member 2 (TM6SF2) p.E167K and the rs641738 membrane bound-o-acyltransferase domain-containing 7 (MBOAT7) polymorphisms are considered the most robust modifiers of NAFLD. However, a forefront frontier in the study of NAFLD heritability is to postulate score-based strategy, building polygenic risk scores (PRS), which aggregate the most relevant genetic determinants of NAFLD and biochemical parameters, with the purpose to foresee patients with greater risk of severe NAFLD, guaranteeing the most highly predictive value, the best diagnostic accuracy and the more precise individualized therapy.

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“…Efforts to determine the regulation and function of lipids and lipidome remodeling have utilized acute stresses such as fasting, circadian rhythm disruption, and cold exposure to rapidly alter tissue lipid profiles (Banfi et al, 2018;BasuRay et al, 2017;Simcox et al, 2017;Xia et al, 2021). Cold exposure is an energy demanding, selective pressure that requires rapid mobilization of lipids as a fuel and signal to activate mitochondrial oxidation (Park et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Systematic assessment of lipid profiles for the discovery of tissue contributors to the circulating lipid pool in cold exposure

Jain

Wade

Ong

et al. 2021

Preprint

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Plasma lipid levels are altered in chronic conditions such as type 2 diabetes and cardiovascular disease as well as acute stresses such as fasting and cold exposure. Advances in mass spectrometry based lipidomics have uncovered the complexity of the plasma lipidome which includes over 500 lipids that serve functional roles including energy substrate and signaling molecule. The plasma lipid pool is maintained through regulation of tissue production, secretion, and uptake. A major challenge is establishing the tissues of origin and uptake for various plasma lipids, which is necessary to determine the lipid function. Using cold exposure as an acute stress, we performed global lipidomics on the plasma and nine tissues that may contribute to the circulating pool. We found that numerous species of plasma acylcarnitines (ACars) and ceramides were significantly changed with cold exposure. Through computational assessment, we identified the liver and brown adipose tissue (BAT) as major contributors and consumers of circulating ACars, in agreement with our previous work. We further identified the kidney and intestine as novel contributors to the circulating ACar pool and validated these findings with gene expression analysis. Regression analysis also identified that the BAT and kidney as regulators of the plasma ceramide pool. These studies provide an adaptable computational tool to assess tissue contribution to the plasma lipid pool. Our findings have implications in understanding the function of plasma ACars and ceramides, which are elevated in metabolic diseases.SummaryThere are over 500 identified lipids in circulating plasma, many without known origin or function. Using untargeted lipidomics on plasma and nine other tissues of cold exposed mice, we identified novel regulation of circulating acylcarnitines through the kidney and intestine, and a multiorgan system that regulates plasma ceramides. Our findings offer new targets for the study and functional characterization of circulating lipids in acute cold exposure and a computational resource for other investigators to explore multi-tissue lipidome remodeling during cold exposure.HighlightsGlobal lipidomics atlas of 9 tissues and plasma demonstrate dynamic shift with cold exposure.Adaptive resource for the selection of extraction method, data processing, and data analysis of multi-tissue global lipidomics data.Regression analysis identified the liver, BAT, intestine, and kidney as regulators of the plasma acylcarnitine pool that are not apparent by lipid levels alone.Acute cold exposure increases plasma ceramide levels, with the BAT and kidney as major contributors

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Hepatic deletion of Mboat7 (LPIAT1) causes activation of SREBP-1c and fatty liver

Cited by 48 publications

References 49 publications

Genetic predisposition similarities between NASH and ASH: Identification of new therapeutic targets

Genetic predisposition similarities between NASH and ASH: Identification of new therapeutic targets

Genetics Is of the Essence to Face NAFLD

Systematic assessment of lipid profiles for the discovery of tissue contributors to the circulating lipid pool in cold exposure

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