Defective Phosphatidylglycerol Remodeling Causes Hepatopathy, Linking Mitochondrial Dysfunction to Hepatosteatosis

Zhang, Xiaoyang; Zhang, Jun; Sun, Haoran; Li, Xueling; Zheng, Yue; Xu, Dan; Wang, Jianing; Jia, Dandan; Han, Xianlin; Li, Feng; Nie, Jia; Shi, Yuguang

doi:10.1016/j.jcmgh.2019.02.002

Cited by 41 publications

(62 citation statements)

References 31 publications

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“…In addition, the species composition of PG is determined post-synthetically by fatty acyl remodeling enzymes, such as the acyltransferase LPGAT. Lysophosphatidylglycerol acyltransferase (LPGAT) deficiency led to hepatopathy, insulin resistance, and non-alcoholic fatty liver disease in mice due to ER stress and mitochondrial dysfunction [46]. Furthermore, PG is the biosynthetic precursor of CL, the hallmark lipid of the mitochondrion.…”

Section: Discussionmentioning

confidence: 99%

Male and Female Animals Respond Differently to High-Fat Diet and Regular Exercise Training in a Mouse Model of Hyperlipidemia

Tóth

Dukay

Péter

et al. 2021

IJMS

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Inappropriate nutrition and a sedentary lifestyle can lead to obesity, one of the most common risk factors for several chronic diseases. Although regular physical exercise is an efficient approach to improve cardiometabolic health, the exact cellular processes are still not fully understood. We aimed to analyze the morphological, gene expression, and lipidomic patterns in the liver and adipose tissues in response to regular exercise. Healthy (wild type on a normal diet) and hyperlipidemic, high-fat diet-fed (HFD-fed) apolipoprotein B-100 (APOB-100)-overexpressing mice were trained by treadmill running for 7 months. The serum concentrations of triglyceride and tumor necrosis factor α (TNFα), as well as the level of lipid accumulation in the liver, were significantly higher in HFD-fed APOB-100 males compared to females. However, regular exercise almost completely abolished lipid accumulation in the liver of hyperlipidemic animals. The expression level of the thermogenesis marker, uncoupling protein-1 (Ucp1), was significantly higher in the subcutaneous white adipose tissue of healthy females, as well as in the brown adipose tissue of HFD-fed APOB-100 females, compared to males. Lipidomic analyses revealed that hyperlipidemia essentially remodeled the lipidome of brown adipose tissue, affecting both the membrane and storage lipid fractions, which was partially restored by exercise in both sexes. Our results revealed more severe metabolic disturbances in HFD-fed APOB-100 males compared to females. However, exercise efficiently reduced the body weight, serum triglyceride levels, expression of pro-inflammatory factors, and hepatic lipid accumulation in our model.

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Section: Discussionmentioning

confidence: 99%

Male and Female Animals Respond Differently to High-Fat Diet and Regular Exercise Training in a Mouse Model of Hyperlipidemia

Tóth

Dukay

Péter

et al. 2021

IJMS

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“…Phosphatidylglycerols are phospholipid precursors of cardiolipins, which have an important role in mitochondrial wall function [ 63 ]. Alterations of phosphatidylglycerols were linked to hepatopathy and hepatic insulin resistance [ 64 ].…”

Section: Discussionmentioning

confidence: 99%

Remodeling Lipids in the Transition from Chronic Liver Disease to Hepatocellular Carcinoma

Ismail

Elfert

Helal

et al. 2020

Cancers

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Hepatocellular carcinoma (HCC) is a worldwide health problem. HCC patients show a 50% mortality within two years of diagnosis. To better understand the molecular pathogenesis at the level of lipid metabolism, untargeted UPLC MS—QTOF lipidomics data were acquired from resected human HCC tissues and their paired nontumor hepatic tissues (n = 46). Blood samples of the same HCC subjects (n = 23) were compared to chronic liver disease (CLD) (n = 15) and healthy control (n = 15) blood samples. The participants were recruited from the National Liver Institute in Egypt. The lipidomics data yielded 604 identified lipids that were divided into six super classes. Five-hundred and twenty-four blood lipids were found as significantly differentiated (p < 0.05 and qFDR p < 0.1) between the three study groups. In the blood of CLD patients compared to healthy control subjects, almost all lipid classes were significantly upregulated. In CLD patients, triacylglycerides were found as the most significantly upregulated lipid class at qFDR p = 1.3 × 10−56, followed by phosphatidylcholines at qFDR p = 3.3 × 10−51 and plasmalogens at qFDR p = 1.8 × 10-46. In contrast, almost all blood lipids were significantly downregulated in HCC patients compared to CLD patients, and in HCC tissues compared to nontumor hepatic tissues. Ceramides were found as the most significant lipid class (qFDR p = 1 × 10−14) followed by phosphatidylglycerols (qFDR p = 3 × 10−9), phosphatidylcholines and plasmalogens. Despite these major differences, there were also common trends in the transitions between healthy controls, CLD and HCC patients. In blood, several mostly saturated triacylglycerides showed a continued increase in the trajectory towards HCC, accompanied by reduced levels of saturated free fatty acids and saturated lysophospatidylcholines. In contrast, the largest overlaps of lipid alterations that were found in both HCC tissue and blood comparisons were decreased levels of phosphatidylglycerols and sphingolipids. This study highlights the specific impact of HCC tumors on the circulating lipids. Such data may be used to target lipid metabolism for prevention, early detection and treatment of HCC in the background of viral-related CLD etiology.

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“…Additionally, we identified StARD7, a mitochondrial PC transporter 11,28,29 , as a novel regulator of mitochondrial PG transport. Our findings offered a logical explanation why depletion of StARD7 caused mitochondrial dysfunction 12 , since PG is a substrate for the synthesis of CL, and CL depletion caused both mitochondrial dysfunction and a loss of crista structure 30,31 . Furthermore, we also identified an unexpected role of ACAT enzymes in facilitating mitochondrial cholesterol transport.…”

Section: Discussionmentioning

confidence: 71%

De NovoLipid Labeling for Comprehensive Analysis of Subcellular Distribution and Trafficking in Live Cells

Zhang¹,

Nie²,

Sun

et al. 2020

Preprint

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Lipids exert dynamic biological functions which are determined both by their fatty acyl compositions and precise spatiotemporal distributions inside the cell. There are more than 1000 lipid species in a typical mammalian cell. However, it remains a daunting task to investigate any of these features in live cells for each of the more than 1000 lipid species. Here we resolved this issue by developing a de novo lipid labeling method for major lipid species, including glycerolipids, glycerophospholipids, and cholesterol esters by using a single fluorescent probe. The method not only allowed us to probe the precise subcellular distribution and trafficking of individual lipid species in live cells, but also uncovered some unexpected biological functions of previously reported lipid metabolic enzymes that were not possible by conventional biochemical methods. We envision that this method will become an indispensable tool for the functional analysis of individual lipid species and numerous lipid metabolic enzymes and transporters in live cells.

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Defective Phosphatidylglycerol Remodeling Causes Hepatopathy, Linking Mitochondrial Dysfunction to Hepatosteatosis

Cited by 41 publications

References 31 publications

Male and Female Animals Respond Differently to High-Fat Diet and Regular Exercise Training in a Mouse Model of Hyperlipidemia

Male and Female Animals Respond Differently to High-Fat Diet and Regular Exercise Training in a Mouse Model of Hyperlipidemia

Remodeling Lipids in the Transition from Chronic Liver Disease to Hepatocellular Carcinoma

De NovoLipid Labeling for Comprehensive Analysis of Subcellular Distribution and Trafficking in Live Cells

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