Perilipin 5 deletion in hepatocytes remodels lipid metabolism and causes hepatic insulin resistance in mice

Keenan, Stacey N; Meex, Ruth C. R.; Lo, Jen C.Y.; Montgomery, Magdalene K; Watt, Matthew J.

doi:10.1016/j.orcp.2018.11.101

Cited by 14 publications

(26 citation statements)

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“…Moreover, we found that the antioxidant role of Plin5 was PI3K/Akt and ERK signaling pathways dependent as Plin5-induced activation of Nrf2-ARE system was significantly inhibited by pharmacologic inhibitor of PI3K/Akt or ERK. In line with our data in pancreatic β-cells, livers of mice with liver-specific Plin5 ablation exhibited activation of JNK and Plin5-null cardiomyocytes showed decreased phosphorylation of PI3K/Akt (24,40). However, in the aortic tissues, ApoE/Plin5 double knockout linked with the activation of PI3K/Akt and MAPK pathways, therefore, may contribute to oxidative stress generation (21).…”

Section: Discussionsupporting

confidence: 86%

“…The detailed mechanism of the antioxidant role of Plin5 via regulating Nrf2-ARE system in β-cells was explored preliminary in the present study. In some tissues, Plin5 has been reported to involve in the regulation of PI3K/Akt or MAPK pathways (p38 MAPK, ERK, and JNK) (21,24,40,44,49), which is the upstream modulators of Nrf2 in pancreatic β-cells (39,41). As evidenced by prior studies, excess ROS production and oxidative stress results in the activation of apoptotic p38 MAPK and JNK signaling, whereas activation of antiapoptotic PI3K/Akt and ERK pathways facilitates the translocation of Nrf2 into the nucleus, thereby activating the Nrf2/ARE pathway and alleviating oxidative damage (50,51).…”

Section: Discussionmentioning

confidence: 99%

“…In the aortic tissues, heart and liver, Plin5 has been reported to associate with PI3K/Akt or MAPK pathway (p38 MAPK, ERK, and JNK) (21,24,40), which involve in modulating oxidative stress (41,42). Here, we first investigated the protein expressions of p-Akt, p-p38, p-ERK1/2, and p-JNK in INS-1 cells incubated with palmitate.…”

Section: Plin5 Induces An Nrf2-are Dependent Antioxidative Stress Defmentioning

confidence: 99%

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Perilipin 5 Reduces Oxidative Damage Associated With Lipotoxicity by Activating the PI3K/ERK-Mediated Nrf2-ARE Signaling Pathway in INS-1 Pancreatic β-Cells

et al. 2020

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Oxidative stress induced by free fatty acid overload in pancreatic β-cells is a potential contributory factor to dysfunction of insulin secretion and apoptotic cell death. Perilipin 5 (Plin5) has been reported to ameliorate oxidative stress-mediated damage in non-insulin-secreting tissues. We tested the hypothesis that Plin5 plays a similar role in pancreatic β-cells, which are extremely sensitive to oxidative stress. Here, our in vitro data showed that Plin5-mediated alleviation of palmitate-triggered apoptosis involves the mitochondrial pathway. And the protective role of Plin5 on β-cells was partially dependent on its modulation in oxidative stress. Upregulation of Plin5 in INS-1 cells decreased reactive oxygen species production, enhanced cellular glutathione levels, and induced expression of antioxidant enzymes glutamate-cysteine ligase catalytic subunit and heme oxygenase-1. However, knocking out of Plin5 abolished all of these beneficial effects. Furthermore, by using the O 2− scavenger MnTMPyP, we verified that altering Plin5 expression impacted lipotoxic cell death partially via modulating oxidative stress. Mechanistic experiments revealed that Plin5 induced Nrf2-ARE system, a master regulator in the cellular adaptive response to oxidative stress, by activating PI3K/Akt and ERK signal pathways, contributing to the increase of antioxidant defense and consequently improving β-cell function and survival in the presence of lipotoxic oxidative stress. Overall, our findings indicate that Plin5 abrogates oxidative damage in INS-1 β-cells during lipotoxic stress partially through the enhancement of antioxidant defense involving the PI3K/Akt and ERK mediated Nrf2-ARE system.

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Section: Discussionsupporting

confidence: 86%

Section: Discussionmentioning

confidence: 99%

Section: Plin5 Induces An Nrf2-are Dependent Antioxidative Stress Defmentioning

confidence: 99%

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Perilipin 5 Reduces Oxidative Damage Associated With Lipotoxicity by Activating the PI3K/ERK-Mediated Nrf2-ARE Signaling Pathway in INS-1 Pancreatic β-Cells

et al. 2020

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“…Liver‐specific Plin5 knockout mice show reduced mitochondria–LDs contacts in hepatocytes, decreased fatty acid oxidation, and reduced triglyceride secretion . Treatment of these mice with a HFD induces greater accumulation of TAG, the activation of JNK, and insulin resistance.…”

Section: Contacts Between Mitochondria and Other Organellesmentioning

confidence: 99%

Metabolic implications of organelle–mitochondria communication

2019

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Cellular organelles are not static but show dynamism—a property that is likely relevant for their function. In addition, they interact with other organelles in a highly dynamic manner. In this review, we analyze the proteins involved in the interaction between mitochondria and other cellular organelles, especially the endoplasmic reticulum, lipid droplets, and lysosomes. Recent results indicate that, on one hand, metabolic alterations perturb the interaction between mitochondria and other organelles, and, on the other hand, that deficiency in proteins involved in the tethering between mitochondria and the ER or in specific functions of the interaction leads to metabolic alterations in a variety of tissues. The interaction between organelles is an emerging field that will permit to identify key proteins, to delineate novel modulation pathways, and to elucidate their implications in human disease.

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“…One of the most-used models of obesity is that of diet-induced obesity (DIO), which—within a few weeks—produces metabolic abnormalities such as insulin resistance and lipid accumulation intracellular lipid droplets in the liver [ 11 , 12 ]. This organelle is involved in the regulation of lipid metabolism, promoting β-oxidation of FA [ 13 ]. Perilipin 5 is a lipid droplet-associated protein (Plin) in this process, which has a relevant role; Plin2 is one of the proteins involved in the lipogenesis process and contributes to lipid droplet growth [ 13 , 14 ].…”

Section: Introductionmentioning

confidence: 99%

EPA/DHA Concentrate by Urea Complexation Decreases Hyperinsulinemia and Increases Plin5 in the Liver of Mice Fed a High-Fat Diet

et al. 2020

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Dietary intake of eicosapentaenoic/docosahexaenoic acid (EPA/DHA) reduces insulin resistance and hepatic manifestations through the regulation of metabolism in the liver. Obese mice present insulin resistance and lipid accumulation in intracellular lipid droplets (LDs). LD-associated proteins perilipin (Plin) have an essential role in both adipogenesis and lipolysis; Plin5 regulates lipolysis and thus contributes to fat oxidation. The purpose of this study was to compare the effects of deodorized refined salmon oil (DSO) and its polyunsaturated fatty acids concentrate (CPUFA) containing EPA and DHA, obtained by complexing with urea, on obesity-induced metabolic alteration. CPUFA maximum content was determined using the Box–Behnken experimental design based on Surface Response Methodology. The optimized CPUFA was administered to high-fat diet (HFD)-fed mice (200 mg/kg/day of EPA + DHA) for 8 weeks. No significant differences (p > 0.05) in cholesterol, glycemia, LDs or transaminase content were found. Fasting insulin and hepatic Plin5 protein level increased in the group supplemented with the EPA + DHA optimized product (38.35 g/100 g total fatty acids) compared to obese mice without fish oil supplementation. The results suggest that processing salmon oil by urea concentration can generate an EPA+DHA dose useful to prevent the increase of fasting insulin and the decrease of Plin5 in the liver of insulin-resistant mice.

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Perilipin 5 deletion in hepatocytes remodels lipid metabolism and causes hepatic insulin resistance in mice

Cited by 14 publications

References 0 publications

Perilipin 5 Reduces Oxidative Damage Associated With Lipotoxicity by Activating the PI3K/ERK-Mediated Nrf2-ARE Signaling Pathway in INS-1 Pancreatic β-Cells

Perilipin 5 Reduces Oxidative Damage Associated With Lipotoxicity by Activating the PI3K/ERK-Mediated Nrf2-ARE Signaling Pathway in INS-1 Pancreatic β-Cells

Metabolic implications of organelle–mitochondria communication

EPA/DHA Concentrate by Urea Complexation Decreases Hyperinsulinemia and Increases Plin5 in the Liver of Mice Fed a High-Fat Diet

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