Delivery of phosphatidylethanolamine blunts stress in hepatoma cells exposed to elevated palmitate by targeting the endoplasmic reticulum

Trentzsch, Marcus; Nyamugenda, Eugene; Miles, Tiffany K.; Griffin, Haven; Russell, Susan; Koss, Brian; Cooney, Kimberly A.; Phelan, Kevin D.; Tackett, Alan J.; Iyer, Srividhya; Boysen, Gunnar; Baldini, Giulia

doi:10.1038/s41420-020-0241-z

Cited by 13 publications

(5 citation statements)

References 55 publications

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“…In our study, livers from HFD animals showed a 6-fold increase in TAGs as well as increased levels of FAs, esterified cholesterols and total cholesterol. Changes in liver phospholipids were reflected by a decrease in PE abundance, which is in accordance with a previous study using a lard-based HFD (refer to Table 1 ) [ 52 ]. Synthesis of PE in liver mitochondria is reliant on the activity of mitofusin-2, which is found to be downregulated in HFD-fed individuals [ 53 ].…”

Section: Discussionsupporting

confidence: 91%

Effects of Lifestyle Intervention in Tissue-Specific Lipidomic Profile of Formerly Obese Mice

Dahdah

González-Franquesa

Samino

et al. 2021

IJMS

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Lipids are highly diverse in their composition, properties and distribution in different biological entities. We aim to establish the lipidomes of several insulin-sensitive tissues and to test their plasticity when divergent feeding regimens and lifestyles are imposed. Here, we report a proton nuclear magnetic resonance (1H-NMR) study of lipid abundance across 4 tissues of C57Bl6J male mice that includes the changes in the lipid profile after every lifestyle intervention. Every tissue analysed presented a specific lipid profile irrespective of interventions. Glycerolipids and fatty acids were most abundant in epididymal white adipose tissue (eWAT) followed by liver, whereas sterol lipids and phosphoglycerolipids were highly enriched in hypothalamus, and gastrocnemius had the lowest content in all lipid species compared to the other tissues. Both when subjected to a high-fat diet (HFD) and after a subsequent lifestyle intervention (INT), the lipidome of hypothalamus showed no changes. Gastrocnemius and liver revealed a pattern of increase in content in many lipid species after HFD followed by a regression to basal levels after INT, while eWAT lipidome was affected mainly by the fat composition of the administered diets and not their caloric density. Thus, the present study demonstrates a unique lipidome for each tissue modulated by caloric intake and dietary composition.

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Section: Discussionsupporting

confidence: 91%

Effects of Lifestyle Intervention in Tissue-Specific Lipidomic Profile of Formerly Obese Mice

Dahdah

González-Franquesa

Samino

et al. 2021

IJMS

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“…In livers of male and female MC4R-HA +/mice kept on HFD liver abundance of lipid droplets visualized by Nile Red staining was increased by 4.8 G 1.4-fold, p < 0.0001 and by 4.7 G 1.7-fold, p < 0.001, respectively, as compared with that of mice constantly kept on LFD (Figures 6F and 6L). We have found that, in mice exposed to HFD, loss of the ER chaperone Grp78/BiP in pericentral hepatocytes parallels hepatosteatosis (Trentzsch et al, 2020). Abundance of Grp78/BiP in pericentral hepatocytes of male and female MC4R-HA +/mice was decreased by 89.0 G 48.4%, iScience Article p < 0.01 and by 87.0 G 20.0%, p < 0.0001, respectively, as compared with that of mice constantly kept on LFD (Figures 6G and 6M).…”

Section: Exposure To Elevated Palmitate Is Sufficient To Induce Loss Of Coxiv and To Disrupt Mitochondrial Function In Primary Hypothalammentioning

confidence: 90%

Selective Survival of Sim1/MC4R Neurons in Diet-Induced Obesity

et al. 2020

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In the melanocortin pathway, melanocortin-4 receptor (MC4R) functions to control energy homeostasis. MC4R is expressed in a sub-population of Sim1 neurons (Sim1/MC4R neurons) and functions in hypothalamic paraventricular nuclei (PVN) to control food intake. Mapping sites of hypothalamic injury in obesity is essential to counteract the disease. In the PVN of male and female mice with diet-induced obesity (DIO) there is neuronal loss. However, the existing subpopulation of PVN Sim1/MC4R neurons is unchanged, but has a loss of mitochondria and MC4R protein. In mice of both sexes with DIO, dietary intervention to re-establish normal weight restores abundance of MC4R protein in Sim1/MC4R neurons and neurogenesis in the PVN. However, the number of non-Sim1/MC4R neurons in the PVN continues to remain decreased. Selective survival and recovery of Sim1/ MC4R neurons after DIO suggests these neurons as preferential target to restore energy homeostasis and of therapy against obesity.

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“…However, a recent study finds instead that palmitate treatment does not activate a classic UPR with altered ER proteostasis in human SH-SY5Y neuroblastoma cells [16]. We also found that, in hepatoma cells and liver, palmitate treatment failed to induce a classic UPR with increased level of ER chaperones [17]. These observations suggest that ER stress and adaptive responses are dependent on the type of trigger and on the cell type, highlighting the need to validate outcomes of lipid stress in hypothalamic neurons empirically.…”

Section: Introductionmentioning

confidence: 46%

Liraglutide Counteracts Endoplasmic Reticulum Stress in Palmitate-Treated Hypothalamic Neurons without Restoring Mitochondrial Homeostasis

Griffin

Sullivan

Barger

et al. 2022

IJMS

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One feature of high-fat diet-induced neurodegeneration in the hypothalamus is an increased level of palmitate, which is associated with endoplasmic reticulum (ER) stress, loss of CoxIV, mitochondrial fragmentation, and decreased abundance of MC4R. To determine whether antidiabetic drugs protect against ER and/or mitochondrial dysfunction by lipid stress, hypothalamic neurons derived from pre-adult mice and neuronal Neuro2A cells were exposed to elevated palmitate. In the hypothalamic neurons, palmitate exposure increased expression of ER resident proteins, including that of SERCA2, indicating ER stress. Liraglutide reverted such altered ER proteostasis, while metformin only normalized SERCA2 expression. In Neuro2A cells liraglutide, but not metformin, also blunted dilation of the ER induced by palmitate treatment, and enhanced abundance and expression of MC4R at the cell surface. Thus, liraglutide counteracts, more effectively than metformin, altered ER proteostasis, morphology, and folding capacity in neurons exposed to fat. In palmitate-treated hypothalamic neurons, mitochondrial fragmentation took place together with loss of CoxIV and decreased mitochondrial membrane potential (MMP). Metformin, but not liraglutide, reverted mitochondrial fragmentation, and both liraglutide and metformin did not protect against either loss of CoxIV abundance or MMP. Thus, ER recovery from lipid stress can take place in hypothalamic neurons in the absence of recovered mitochondrial homeostasis.

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Delivery of phosphatidylethanolamine blunts stress in hepatoma cells exposed to elevated palmitate by targeting the endoplasmic reticulum

Cited by 13 publications

References 55 publications

Effects of Lifestyle Intervention in Tissue-Specific Lipidomic Profile of Formerly Obese Mice

Effects of Lifestyle Intervention in Tissue-Specific Lipidomic Profile of Formerly Obese Mice

Selective Survival of Sim1/MC4R Neurons in Diet-Induced Obesity

Liraglutide Counteracts Endoplasmic Reticulum Stress in Palmitate-Treated Hypothalamic Neurons without Restoring Mitochondrial Homeostasis

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