Perilipin 5, a Lipid Droplet-binding Protein, Protects Heart from Oxidative Burden by Sequestering Fatty Acid from Excessive Oxidation

Kuramoto, Kenta; Okamura, Tomoo; Yamaguchi, Tomohiro; Nakamura, Tomoe Y.; Wakabayashi, Shigeo; Morinaga, Hidetaka; Nomura, Masatoshi; Yanase, Toshihiko; Otsu, Kinya; Usuda, Nobuteru; Matsumura, Shigenobu; Inoue, Kazuo; Fushiki, Tohru; Kojima, Yumiko; Hashimoto, Takeshi; Sakai, Fumie; Hirose, Fumiko; Osumi, Takashi

doi:10.1074/jbc.m111.328708

Cited by 203 publications

(231 citation statements)

References 46 publications

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“…54 Knockout of Plin5 in mice increases oxidative stress to the heart. 20 It has been reported that the activation of AMPK promotes the phosphorylation of the transcription factor Nrf2, which triggers the translocation of Nrf2 from the cytoplasm into the nucleus, leading to its binding to ARE and the induction of expression of target genes. 66 In this report, we demonstrated that the expression of exogenous Plin5 reduced cellular ROS and LPO, and attenuated oxidative stress in HSC by elevating the level of cellular GSH and GSH/GSSG ratio.…”

Section: Plin5 Restores Ld Formation In Hscmentioning

confidence: 99%

“…18,19 LDs prevent excess production of ROS by sequestering fatty acids from oxidation and hence suppress oxidative stress. 20 The aim of this study is aimed at elucidating the role of Plin5 in inhibiting HSC activation and exploring underlying mechanisms, we hypothesize that on activation during liver injury, the loss of LDs and the depletion of cellular lipids in HSC are coupled to an apparent reduction in gene expression of Plin5. The expression of exogenous Plin5 could restore the formation of LDs and elevate cellular lipid content in HSC, leading to inhibition of the activation of HSC.…”

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confidence: 99%

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Perilipin 5 restores the formation of lipid droplets in activated hepatic stellate cells and inhibits their activation

Lin

Chen

2016

Laboratory Investigation

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Hepatic stellate cells (HSC) are major effectors during hepatic fibrogenesis. The activation of HSC is coupled to the loss of lipid droplets (LDs), which are specialized organelles composed of neutral lipids surrounded by perilipins. LDs have emerged as a focal point of interest in understanding the metabolic regulation of intrahepatic lipids during lipid-mediated liver fibrogenesis. Perilipin 5 (Plin5) is a newly identified LD protein in the perilipin family, which plays a key role in regulating aspects of intracellular trafficking, signaling, and cytoskeletal organization in hepatocytes. Recent work in Plin5 knockout mice suggests a role in high fat diet-induced hepatic lipotoxicity. The current report is to evaluate the impact of Plin5 on HSC activation and to elucidate the underlying mechanisms. We now show that high fat diet-induced liver fibrosis is accompanied by an approximate 75% reduction in Plin5 in HSC, and that spontaneous activation of primary HSC produces temporally coincident loss of Plin5 expression and LD depletion. As modulating lipid content in HSC is a suggested strategy for inhibition of HSC activation and treatment of hepatic fibrosis, we asked whether exogenous Plin5 expression in primary HSC would reverse the activation phenotype and promote LD formation. Recombinant lentiviral Plin5 expression in primary mouse HSC restored the formation of LDs, increased lipid content by inducing expression of pro-lipogenic genes and suppressing expression of pro-lipolytic genes, and suppressed HSC activation (~two fold reduction in expression of procollagen and α-smooth muscle actin, two unique biomarkers for activated HSC). In addition, the expression of exogenous Plin5 in HSC attenuated cellular oxidative stress by reducing cellular reactive oxygen species, elevating cellular glutathione, and inducing gene expression of glutamate-cysteine ligase. Taken together, our results indicate that expression of Plin5 plays a critical role in the formation of LDs, the elevation of lipid content in HSC, and the inhibition of the activation of HSC.

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Section: Plin5 Restores Ld Formation In Hscmentioning

confidence: 99%

mentioning

confidence: 99%

Perilipin 5 restores the formation of lipid droplets in activated hepatic stellate cells and inhibits their activation

Lin

Chen

2016

Laboratory Investigation

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“…PLIN5 expression is also reported in pancreatic beta cells and hepatic stellate cells [35,36]. A unique feature with PLIN5 is that mitochondria are physically recruited to lipid droplets expressing high PLIN5 (Figure 2) [37,38]. Its expression is regulated by PPAR-alpha, and most importantly, PLIN5 plays roles in regulating cellular fat oxidation.…”

Section: Plin5mentioning

confidence: 86%

“…PLIN5 stabilizes lipid droplets by sequestrating faty acids, and because PLIN5 can recruit mitochondria to lipid droplet surface, it facilitates to release faty acids to mitochondria for the oxidation [39]. Given its gatekeeper roles on the lipid oxidation, it has been suggested that PLIN5 could protect cardiac myocytes and hepatocytes from oxidative stress [38,40]. PLIN5 leads several modiications on the lipid metabolism as well as insulin sensitivity, and details are discussed in a separate paragraph.…”

Section: Plin5mentioning

confidence: 99%

Role of Lipid Droplet Proteins in the Development of NAFLD and Hepatic Insulin Resistance

Minehira¹,

Gual²

2018

Non-Alcoholic Fatty Liver Disease - Molecular Bases, Prevention and Treatment

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NAFLD is diagnosed, when the liver fat exceeds more than 5% of liver weight. Inside of hepatocytes, these fats are stored in cytosolic lipid droplets. The lipid droplets can be formed from a bud, vesicles of the lipid bilayer, which lines at a vicinity of the endoplasmic reticulum (ER). On the surface of droplets, there are several structural/ functional proteins such as lipid droplet proteins, lipogenic enzymes, and lipases. Interestingly, the lipid droplet proteins seem to have great impact on a development of NAFLD. Some proteins can interact with transcriptional factors such as SREBP1c and PPAR-alpha/gamma, and some proteins strongly impact a mitochondrial structure. As a result, the lipid droplet proteins highly inluence lipid handling and faty acid oxidation in hepatocytes. This chapter will elucidate our recent understanding of the role of each lipid droplet protein in faty liver formation and in hepatic insulin resistance. Existing information on genetically modiied animals as well as on human NAFLD was reviewed on Perilipin families, CIDE proteins, Seipin, and PNPLAs. Finally, the chapter will discuss how the lipid droplet proteins could potentially lead/protect from hepatic insulin resistance via abnormal accumulation of ceramides and diacylglycerols, autophagy, ER stress, and oxidative stress.

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“…Feeding unsaturated FA, protects against saturated FA-induced cell death by sequestering lipids in intracellular droplets [85,86] Perlipins regulate FA-storage to regulate and maintain normal oxidative balance [87,88] MicroRNA FA-induced changes in miR regulation results in insulin resistance [89] Mitochondrial function FA-induced mitochondrial fragmentation and increased reactive oxygen species (ROS) [90] * FA: fatty acid; TAG: triacylglycerol; WD: western diet…”

Section: Apoptotic Pathwaysmentioning

confidence: 99%

Lipid-induced cardiovascular diseases

Manandhar¹,

Ju²,

Choi³

et al. 2017

J Cardiol Cardiovasc Med

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Cardiovascular diseases are the leading cause of death worldwide. There are many evidences that the dysfunctioning lipotoxicity is the one of major factors of cardiovascular diseases such as, atherosclerosis, hypertension, and coronary heart disease. Obesity and diabetes increase circulating lipids that are likely with more generation of toxic intermediates, which leading to the complications associated with cardiovascular diseases. Indeed, lipotoxicity is a metabolic syndrome caused by abnormal lipid accumulation, which leads to cellular dysfunction and necrosis. Here we review the factors that induced pathogenesis of cardiovascular diseases by lipid accumulation and the mechanisms underlying the lipotoxicity.

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Perilipin 5, a Lipid Droplet-binding Protein, Protects Heart from Oxidative Burden by Sequestering Fatty Acid from Excessive Oxidation

Cited by 203 publications

References 46 publications

Perilipin 5 restores the formation of lipid droplets in activated hepatic stellate cells and inhibits their activation

Perilipin 5 restores the formation of lipid droplets in activated hepatic stellate cells and inhibits their activation

Role of Lipid Droplet Proteins in the Development of NAFLD and Hepatic Insulin Resistance

Lipid-induced cardiovascular diseases

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