Oleate protects beta-cells from the toxic effect of palmitate by activating pro-survival pathways of the ER stress response

Sargsyan, Ernest; Artemenko, Konstantin A.; Manukyan, Levon; Bergquist, Jonas; Bergsten, Peter

doi:10.1016/j.bbalip.2016.06.012

Cited by 45 publications

(38 citation statements)

References 62 publications

(73 reference statements)

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“…Although it has previously been suggested that astaxanthin may attenuate ER stress in the liver [28], its effects on pancreatic β-cell stress remain to be elucidated. Palmitate, a saturated fatty acid, exacerbated ER stress, as well as oxidative stress, in MIN6 cells as previously reported [29,30,31,32]. Interestingly, an antioxidant, NAC, failed to suppress the ER stress enhanced by palmitate, whereas astaxanthin, another antioxidant, attenuated this enhancement of ER stress in addition to oxidative stress.…”

Section: Discussionsupporting

confidence: 83%

The Novel Mechanisms Concerning the Inhibitions of Palmitate-Induced Proinflammatory Factor Releases and Endogenous Cellular Stress with Astaxanthin on MIN6 β-Cells

et al. 2017

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Astaxanthin, an antioxidant agent, can protect pancreatic β-cells of db/db mice from glucotoxicity and resolve chronic inflammation in adipose tissue. Nonetheless, the effects of astaxanthin on free-fatty-acid-induced inflammation and cellular stress in β-cells remain to be demonstrated. Meanwhile, palmitate enhances the secretion of pro-inflammatory adipokines monocyte chemoattractant protein-1 (MCP-1) and vascular endothelial growth factor (VEGF120). We therefore investigated the influence of astaxanthin on palmitate-stimulated MCP-1 and VEGF120 secretion in mouse insulinoma (MIN6) pancreatic β-cells. Furthermore, whether astaxanthin prevents cellular stress in MIN6 cells was also assessed. Pre-treatment with astaxanthin or with N-acetyl-cysteine (NAC) which is an antioxidant drug, significantly attenuated the palmitate-induced MCP-1 release through downregulation of phosphorylated c-Jun NH2-terminal protein kinase (JNK) pathways, and suppressed VEGF120 through the PI3K/Akt pathways relative to the cells stimulated with palmitate alone. In addition, palmitate significantly upregulated homologous protein (CHOP) and anti-glucose-regulated protein (GRP78), which are endoplasmic reticulum (ER) stress markers, in MIN6 cells. On the other hand, astaxanthin attenuated the increased CHOP content, but further up-regulated palmitate-stimulated GRP78 protein expression. By contrast, NAC had no effects on either CHOP or GRP78 enhancement induced by palmitate in MIN6 cells. In conclusion, astaxanthin diminishes the palmitate-stimulated increase in MCP-1 secretion via the downregulation of JNK pathways in MIN6 cells, and affects VEGF120 secretion through PI3K/Akt pathways. Moreover, astaxanthin can prevent not only oxidative stress caused endogenously by palmitate but also ER stress, which NAC fails to attenuate, via upregulation of GRP78, an ER chaperon.

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Section: Discussionsupporting

confidence: 83%

The Novel Mechanisms Concerning the Inhibitions of Palmitate-Induced Proinflammatory Factor Releases and Endogenous Cellular Stress with Astaxanthin on MIN6 β-Cells

et al. 2017

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“…Clearly, inhibition of FAM3A‐CaM‐FOXA2 axis links mitochondrial dysfunction to PDX1 repression and pancreatic β cell dysfunction under obese condition. It has long been known that saturated fatty acid such as palmitate exerts deleterious effects, whereas unsaturated fatty acid such as oleate has beneficial effects on pancreatic β cell functions . Activation of miR‐423‐5p to repress FAM3A signaling pathway provides a novel explanation for palmitate‐induced nuclear exclusion of FOXA2 in pancreatic β cells .…”

Section: Discussionmentioning

confidence: 99%

FAM3A plays crucial roles in controlling PDX1 and insulin expressions in pancreatic beta cells

et al. 2020

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So far, the mechanism that links mitochondrial dysfunction to PDX1 inhibition in the pathogenesis of pancreatic β cell dysfunction under diabetic condition remains largely unclear. This study determined the role of mitochondrial protein FAM3A in regulating PDX1 expression in pancreatic β cells using gain‐ and loss‐of function methods in vitro and in vivo. Within pancreas, FAM3A is highly expressed in β, α, δ, and pp cells of islets. Islet FAM3A expression was correlated with insulin expression under physiological and diabetic conditions. Mice with specific knockout of FAM3A in islet β cells exhibited markedly blunted insulin secretion and glucose intolerance. FAM3A‐deficient islets showed significant decrease in PDX1 expression, and insulin expression and secretion. FAM3A overexpression upregulated PDX1 and insulin expressions, and augmented insulin secretion in cultured islets and β cells. Mechanistically, FAM3A enhanced ATP production to elevate cellular Ca2+ level and promote insulin secretion. Furthermore, FAM3A‐induced ATP release activated CaM to function as a co‐activator of FOXA2, stimulating PDX1 gene transcription. In conclusion, FAM3A plays crucial roles in controlling PDX1 and insulin expressions in pancreatic β cells. Inhibition of FAM3A will trigger mitochondrial dysfunction to repress PDX1 and insulin expressions.

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“…Palmitate also impairs MDA‐MB‐231 cell proliferation and activates apoptosis (Baumann et al ., 2016; Hardy et al ., 2000, 2003; Kourtidis et al ., 2009; Wu et al ., 2017) via a number of mechanisms, including ER stress (Baumann et al ., 2016; Boslem et al ., 2011), impaired autophagy (RostamiRad et al ., 2018; Wu et al ., 2017), altered NAD metabolism (Penke et al ., 2017), and ceramide synthesis (Luo et al ., 2017). Importantly, many of the deleterious effects of palmitate on cellular function are mitigated by cotreatment with other FAs, in particular the monounsaturated FA oleate (Colvin et al ., 2017; Kim et al ., 2017; Penke et al ., 2017; Sargsyan et al ., 2016), which itself is pro‐proliferative and activates phosphoinositide 3‐kinase signaling (Hardy et al ., 2000). …”

Section: Discussionmentioning

confidence: 99%

“…Our results shed new light on the contribution of FA oxidation in MCF‐7 cells where pharmacological inhibition of FA oxidation sensitized MCF‐7 cells to palmitate‐induced apoptosis and suggests that targeting FA oxidation is an attractive therapeutic strategy in BrCa. The addition or presence of oleate ameliorates the cytotoxic effects of palmitate (Capel et al ., 2016; Colvin et al ., 2017; Kim et al ., 2017; Kwon and Querfurth, 2015; Penke et al ., 2017; Sargsyan et al ., 2016). Proposed mechanisms for these observations include attenuating palmitate‐induced ER stress (Colvin et al ., 2017), preventing activation of the unfolded protein response (Sommerweiss et al ., 2013), activating prosurvival pathways of ER stress (Sargsyan et al ., 2016), restoring insulin stimulated protein kinase B (Akt) signaling (Capel et al ., 2016), and activating AMP‐activated protein kinase and mechanistic target of rapamycin signaling (Kwon and Querfurth, 2015).…”

Section: Discussionmentioning

confidence: 99%

“…The addition or presence of oleate ameliorates the cytotoxic effects of palmitate (Capel et al ., 2016; Colvin et al ., 2017; Kim et al ., 2017; Kwon and Querfurth, 2015; Penke et al ., 2017; Sargsyan et al ., 2016). Proposed mechanisms for these observations include attenuating palmitate‐induced ER stress (Colvin et al ., 2017), preventing activation of the unfolded protein response (Sommerweiss et al ., 2013), activating prosurvival pathways of ER stress (Sargsyan et al ., 2016), restoring insulin stimulated protein kinase B (Akt) signaling (Capel et al ., 2016), and activating AMP‐activated protein kinase and mechanistic target of rapamycin signaling (Kwon and Querfurth, 2015). Oleate treatment in a range of cells also modulates palmitate metabolism including stimulating TAG synthesis, preventing diacylglycerol accumulation (Capel et al ., 2016; Kwon et al ., 2014), and preventing mitochondrial reactive oxygen species production and dysfunction (Kwon et al ., 2014).…”

Section: Discussionmentioning

confidence: 99%

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Heterogeneity of fatty acid metabolism in breast cancer cells underlies differential sensitivity to palmitate‐induced apoptosis

et al. 2018

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Breast cancer (BrCa) metabolism is geared toward biomass synthesis and maintenance of reductive capacity. Changes in glucose and glutamine metabolism in BrCa have been widely reported, yet the contribution of fatty acids (FAs) in BrCa biology remains to be determined. We recently reported that adipocyte coculture alters MCF‐7 and MDA‐MB‐231 cell metabolism and promotes proliferation and migration. Since adipocytes are FA‐rich, and these FAs are transferred to BrCa cells, we sought to elucidate the FA metabolism of BrCa cells and their response to FA‐rich environments. MCF‐7 and MDA‐MB‐231 cells incubated in serum‐containing media supplemented with FAs accumulate extracellular FAs as intracellular triacylglycerols (TAG) in a dose‐dependent manner, with MDA‐MB‐231 cells accumulating more TAG. The differences in TAG levels were a consequence of distinct differences in intracellular partitioning of FAs, and not due to differences in the rate of FA uptake. Specifically, MCF‐7 cells preferentially partition FAs into mitochondrial oxidation, whereas MDA‐MB‐231 cells partition FAs into TAG synthesis. These differences in intracellular FA handling underpin differences in the sensitivity to palmitate‐induced lipotoxicity, with MDA‐MB‐231 cells being highly sensitive, whereas MCF‐7 cells are partially protected. The attenuation of palmitate‐induced lipotoxicity in MCF‐7 cells was reversed by inhibition of FA oxidation. Pretreatment of MDA‐MB‐231 cells with FAs increased TAG synthesis and reduced palmitate‐induced apoptosis. Our results provide novel insight into the potential influences of obesity on BrCa biology, highlighting distinct differences in FA metabolism in MCF‐7 and MDA‐MB‐231 cells and how lipid‐rich environments modulate these effects.

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Oleate protects beta-cells from the toxic effect of palmitate by activating pro-survival pathways of the ER stress response

Cited by 45 publications

References 62 publications

The Novel Mechanisms Concerning the Inhibitions of Palmitate-Induced Proinflammatory Factor Releases and Endogenous Cellular Stress with Astaxanthin on MIN6 β-Cells

The Novel Mechanisms Concerning the Inhibitions of Palmitate-Induced Proinflammatory Factor Releases and Endogenous Cellular Stress with Astaxanthin on MIN6 β-Cells

FAM3A plays crucial roles in controlling PDX1 and insulin expressions in pancreatic beta cells

Heterogeneity of fatty acid metabolism in breast cancer cells underlies differential sensitivity to palmitate‐induced apoptosis

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