The mPlrp2 and mClps genes are involved in the hydrolysis of retinyl esters in the mouse liver

Pang, Wenqiang; Zhang, Ying; Wang, Shiming; Jia, Ai‐Qun; Dong, Wei; Cai, Chun; Hua, Zichun; Zhang, Jianfa

doi:10.1194/jlr.m010082

Cited by 15 publications

(13 citation statements)

References 34 publications

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“…In the meantime, SAM is one of the substrates for DNMTs, high levels of SAM increase the activity of DNMTs, which is reflected in the global methylation experiment. Apart from DNA methylation, Hcy is associated with histone methylation, which alters the expression of remodeling genes 34 . Our study showed an increase in H3K27me3 on CFTR promoter and the expression of EZH2 in CBS +/- mice.…”

Section: Discussionmentioning

confidence: 99%

Homocysteine activates autophagy by inhibition of CFTR expression via interaction between DNA methylation and H3K27me3 in mouse liver

Jiao

Yang

et al. 2018

Cell Death Dis

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Elevated homocysteine (Hcy) levels have been reported to be involved in liver injury, and autophagy plays an important role in normal hepatic physiology and pathophysiology, but the mechanism underlying Hcy regulated autophagy is currently unknown. In this study, CBS+/- mice were fed with regular diet for 12 weeks to establish a hyperhomocysteinemia (HHcy) model and HL-7702 cells were treated with Hcy, we found that Hcy increases autophagy and aggravates liver injury by downregulation of cystic fibrosis transmembrane conductance regulator (CFTR) expression in vivo and in vitro. Overexpression of CFTR inhibited the formation of autophagosomes and the expression of autophagy-related proteins BECN1, LC3-II/I and Atg12, while the expression of p62 increased in Hcy-treated hepatocytes and CBS+/- mice injected with lentivirus expressing CFTR. Further study showed that CFTR expression is regulated by the interaction of DNA methyltransferase 1 (DNMT1) and enhancer of zeste homolog 2 (EZH2), which, respectively, regulate DNA methylation and histone H3 lysine 27 trimethylation (H3K27me3). In conclusion, our study showed that Hcy activates autophagy by inhibition of CFTR expression via interaction between H3K27me3 and DNA methylation in the mouse liver. These findings provide new insight into the mechanism of Hcy-induced autophagy in liver injury.

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Section: Discussionmentioning

confidence: 99%

Homocysteine activates autophagy by inhibition of CFTR expression via interaction between DNA methylation and H3K27me3 in mouse liver

Jiao

Yang

et al. 2018

Cell Death Dis

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“…However, it was also reported that expression of mutant PNPLA3 in HSCs leads to the depletion of retinol, but higher lipid droplet content was accompanied by increased release of proinflammatory cytokines, suggesting a role for this mutation in HSC activation [46]. Other enzymes probably involved in retinol mobilization are lipoprotein lipase (LPL), pancreatic-related protein 2 (mPlrp2), and procolipase (mClps), which were all reported to be significantly increased in activated HSCs [47,48]. Interestingly, in rat HSCs, seven days after activation of the culture by plating on a plastic surface, retinyl loss was not accompanied by triglyceride decrease [49].…”

Section: Hepatic Stellate Cellsmentioning

confidence: 99%

Metabolic Hallmarks of Hepatic Stellate Cells in Liver Fibrosis

Khomich

Ivanov

Bartosch

2019

Cells

160

154

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Liver fibrosis is a regenerative process that occurs after injury. It is characterized by the deposition of connective tissue by specialized fibroblasts and concomitant proliferative responses. Chronic damage that stimulates fibrogenic processes in the long-term may result in the deposition of excess matrix tissue and impairment of liver functions. End-stage fibrosis is referred to as cirrhosis and predisposes strongly to the loss of liver functions (decompensation) and hepatocellular carcinoma. Liver fibrosis is a pathology common to a number of different chronic liver diseases, including alcoholic liver disease, non-alcoholic fatty liver disease, and viral hepatitis. The predominant cell type responsible for fibrogenesis is hepatic stellate cells (HSCs). In response to inflammatory stimuli or hepatocyte death, HSCs undergo trans-differentiation to myofibroblast-like cells. Recent evidence shows that metabolic alterations in HSCs are important for the trans-differentiation process and thus offer new possibilities for therapeutic interventions. The aim of this review is to summarize current knowledge of the metabolic changes that occur during HSC activation with a particular focus on the retinol and lipid metabolism, the central carbon metabolism, and associated redox or stress-related signaling pathways.Most of the progress that has been made in the identification of the molecular mechanisms underlying fibrosis is based on the use of in vitro model systems using tissue culture-adapted HSC lines, primary HSC preparations, and a number of in vivo models such as animals being fed high-fat/cholesterol or choline-deficient diets, animals that undergo bile duct ligation, treatment with ethanol, CCl 4 or other chemical agents, or transgenic animals [5]. Hepatic Stellate CellsThe cell type that is predominantly responsible for fibrotic processes is hepatic stellate cells (HSCs), a mesenchymal cell population that constitutes 5-10% of the total number of cells in the liver (Figure 1). HSCs are located in the perisinusoidal space (space of Disse) and are surrounded by hepatocytes and sinusoidal endothelial cells [6,7]. Their main functions are the secretion of laminin, proteoglycans, and type IV collagen to form basement membrane-like structures. Quiescent HSCs start to proliferate and undergo trans-differentiation into contractile myofibroblasts in response to paracrine stimulation by neighboring cell types, including Kupffer cells, hepatocytes, platelets, leukocytes, and sinusoidal endothelial cells. Kupffer cells can stimulate activation and proliferation of HSCs through the actions of cytokines, and in particular transforming growth factor β1 (TGFβ1), interleukin 1 (IL-1), tumor necrosis factor (TNF), reactive oxygen species (ROS) and lipid peroxides [6,8]. Hepatocytes are an important source of inflammatory lipid peroxides in liver diseases. Platelets release pro-fibrogenic growth factors such as platelet-derived growth factor (PDGF), TGFβ1, and epidermal growth factor (EGF). Neutrophils are an important source of RO...

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“…However, few details of how this is achieved are known, e.g., it is unknown how retinol gets in and out of HSC and which (molecular) signals control this. Mobilization of retinol from lipid droplets in HSC is catalyzed by REHs, and several enzymes are implicated in this process, including adipose triglyceride lipase (ATGL/PNPLA2) [ 44 ], patatin-like phospholipase domain-containing 3 (PNPLA3) [ 44 , 45 , 46 ], and hormone-sensitive lipase (HSL) [ 47 , 48 ]. Interestingly, genetic studies have identified the PNPLA3-I148M variant as a prominent genetic factor associated with NAFLD, and even more prominently with disease progression within NAFLD to NASH and NASH-associated cirrhosis [ 49 , 50 , 51 ].…”

Section: Vitamin a Uptake Storage And Metabolismmentioning

confidence: 99%

Disturbed Vitamin A Metabolism in Non-Alcoholic Fatty Liver Disease (NAFLD)

et al. 2017

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Vitamin A is required for important physiological processes, including embryogenesis, vision, cell proliferation and differentiation, immune regulation, and glucose and lipid metabolism. Many of vitamin A’s functions are executed through retinoic acids that activate transcriptional networks controlled by retinoic acid receptors (RARs) and retinoid X receptors (RXRs).The liver plays a central role in vitamin A metabolism: (1) it produces bile supporting efficient intestinal absorption of fat-soluble nutrients like vitamin A; (2) it produces retinol binding protein 4 (RBP4) that distributes vitamin A, as retinol, to peripheral tissues; and (3) it harbors the largest body supply of vitamin A, mostly as retinyl esters, in hepatic stellate cells (HSCs). In times of inadequate dietary intake, the liver maintains stable circulating retinol levels of approximately 2 μmol/L, sufficient to provide the body with this vitamin for months. Liver diseases, in particular those leading to fibrosis and cirrhosis, are associated with impaired vitamin A homeostasis and may lead to vitamin A deficiency. Liver injury triggers HSCs to transdifferentiate to myofibroblasts that produce excessive amounts of extracellular matrix, leading to fibrosis. HSCs lose the retinyl ester stores in this process, ultimately leading to vitamin A deficiency. Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome and is a spectrum of conditions ranging from benign hepatic steatosis to non-alcoholic steatohepatitis (NASH); it may progress to cirrhosis and liver cancer. NASH is projected to be the main cause of liver failure in the near future. Retinoic acids are key regulators of glucose and lipid metabolism in the liver and adipose tissue, but it is unknown whether impaired vitamin A homeostasis contributes to or suppresses the development of NAFLD. A genetic variant of patatin-like phospholipase domain-containing 3 (PNPLA3-I148M) is the most prominent heritable factor associated with NAFLD. Interestingly, PNPLA3 harbors retinyl ester hydrolase activity and PNPLA3-I148M is associated with low serum retinol level, but enhanced retinyl esters in the liver of NAFLD patients. Low circulating retinol in NAFLD may therefore not reflect true “vitamin A deficiency”, but rather disturbed vitamin A metabolism. Here, we summarize current knowledge about vitamin A metabolism in NAFLD and its putative role in the progression of liver disease, as well as the therapeutic potential of vitamin A metabolites.

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The mPlrp2 and mClps genes are involved in the hydrolysis of retinyl esters in the mouse liver

Cited by 15 publications

References 34 publications

Homocysteine activates autophagy by inhibition of CFTR expression via interaction between DNA methylation and H3K27me3 in mouse liver

Homocysteine activates autophagy by inhibition of CFTR expression via interaction between DNA methylation and H3K27me3 in mouse liver

Metabolic Hallmarks of Hepatic Stellate Cells in Liver Fibrosis

Disturbed Vitamin A Metabolism in Non-Alcoholic Fatty Liver Disease (NAFLD)

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