Glucolipotoxicity in INS-1E cells is counteracted by carnitine palmitoyltransferase 1 over-expression

Sol, E-ri Maria; Sargsyan, Ernest; Akusjärvi, Göran; Bergsten, Peter

doi:10.1016/j.bbrc.2008.08.013

Cited by 23 publications

(22 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…When beta cells are simultaneous exposed to high levels of glucose and FFA, a transient increase of malonyl-CoA is believed to block acyl-CoA transport into the mitochondria and ultimately block FAO since malonyl-CoA inhibits CPT-1 [19,21]. A report showing that over-expression of CPT-1 counteracted beta cell glucolipotoxicity also suggests that transportation of acyl-CoA to mitochondria may be impaired in HG/ PA-treated cells [38]. In addition to impaired transportation, oxida- tion of FFAs in mitochondria may be incomplete in beta cells since incomplete FAO was reported to be a contributor to FFA-induced insulin resistance [31].…”

Section: Discussionmentioning

confidence: 99%

Supplement of TCA cycle intermediates protects against high glucose/palmitate-induced INS-1 beta cell death

Choi

Lee

Hwang

et al. 2011

Archives of Biochemistry and Biophysics

View full text Add to dashboard Cite

Section: Discussionmentioning

confidence: 99%

Supplement of TCA cycle intermediates protects against high glucose/palmitate-induced INS-1 beta cell death

Choi

Lee

Hwang

et al. 2011

Archives of Biochemistry and Biophysics

View full text Add to dashboard Cite

“…Approaches used to enhance FA oxidation and triacylglyceride (TAG) storage have demonstrated significant alterations in the effects of exogenous saturated FAs on ␤-cell function (5,35,54). Studies have also shown that regulation of FA structure may participate in modulating the effects of FAs on ␤-cells.…”

mentioning

confidence: 98%

Modulation of palmitate-induced endoplasmic reticulum stress and apoptosis in pancreatic β-cells by stearoyl-CoA desaturase and Elovl6

Green

Olson²

2011

American Journal of Physiology-Endocrinology and Metabolism

105

View full text Add to dashboard Cite

Induction of endoplasmic reticulum (ER) stress and apoptosis by elevated exogenous saturated fatty acids (FAs) plays a role in the pathogenesis of β-cell dysfunction and loss of islet mass in type 2 diabetes. Regulation of monounsaturated FA (MUFA) synthesis through FA desaturases and elongases may alter the susceptibility of β-cells to saturated FA-induced ER stress and apoptosis. Herein, stearoyl-CoA desaturase (SCD)1 and SCD2 mRNA expression were shown to be induced in islets from prediabetic hyperinsulinemic Zucker diabetic fatty (ZDF) rats, whereas SCD1, SCD2, and fatty acid elongase 6 (Elovl6) mRNA levels were markedly reduced in diabetic ZDF rat islets. Knockdown of SCD in INS-1 β-cells decreased desaturation of palmitate to MUFA, lowered FA partitioning into complex neutral lipids, and increased palmitate-induced ER stress and apoptosis. Overexpression of SCD2 increased desaturation of palmitate to MUFA and attenuated palmitate-induced ER stress and apoptosis. Knockdown of Elovl6 limited palmitate elongation to stearate, increasing palmitoleate production and attenuating palmitate-induced ER stress and apoptosis, whereas overexpression of Elovl6 increased palmitate elongation to stearate and palmitate-induced ER stress and apoptosis. Overall, these data support the hypothesis that enhanced MUFA synthesis via upregulation of SCD2 activity can protect β-cells from elevated saturated FAs, as occurs in prediabetic states. Overt type 2 diabetes is associated with diminished islet expression of SCD and Elovl6, and this can disrupt desaturation of saturated FAs to MUFAs, rendering β-cells more susceptible to saturated FA-induced ER stress and apoptosis.

show abstract

“…Because accumulation of palmitate-derived metabolites within muscle cells is associated with decreased mitochondrial FA oxidative capacity, increasing LCFA oxidation may exert a protective effect. Additionally, contradictory results have been reported concerning the impact of a modulation of mitochondrial LCFA oxidation on palmitate-induced apoptosis in cardiomyocytes (11,22) and pancreatic ␤-cells (13,24,25). This question has never been addressed in skeletal muscle cells.…”

mentioning

confidence: 99%

Increased Mitochondrial Fatty Acid Oxidation Is Sufficient to Protect Skeletal Muscle Cells from Palmitate-induced Apoptosis

Hénique

Mansouri²,

Fumey³

et al. 2010

Journal of Biological Chemistry

139

118

View full text Add to dashboard Cite

The mechanisms underlying the protective effect of monounsaturated fatty acids (e.g. oleate) against the lipotoxic action of saturated fatty acids (e.g. palmitate) in skeletal muscle cells remain poorly understood. This study aimed to examine the role of mitochondrial long-chain fatty acid (LCFA) oxidation in mediating oleate's protective effect against palmitate-induced lipotoxicity. CPT1 (carnitine palmitoyltransferase 1), which is the key regulatory enzyme of mitochondrial LCFA oxidation, is inhibited by malonyl-CoA, an intermediate of lipogenesis. We showed that expression of a mutant form of CPT1 (CPT1mt), which is active but insensitive to malonyl-CoA inhibition, in C2C12 myotubes led to increased LCFA oxidation flux even in the presence of high concentrations of glucose and insulin. Furthermore, similar to preincubation with oleate, CPT1mt expression protected muscle cells from palmitate-induced apoptosis and insulin resistance by decreasing the content of deleterious palmitate derivates (i.e. diacylglycerols and ceramides). Oleate preincubation exerted its protective effect by two mechanisms: (i) in contrast to CPT1mt expression, oleate preincubation increased the channeling of palmitate toward triglycerides, as a result of enhanced diacylglycerol acyltransferase 2 expression, and (ii) oleate preincubation promoted palmitate oxidation through increasing CPT1 expression and modulating the activities of acetyl-CoA carboxylase and AMP-activated protein kinase. In conclusion, we demonstrated that targeting mitochondrial LCFA oxidation via CPT1mt expression leads to the same protective effect as oleate preincubation, providing strong evidence that redirecting palmitate metabolism toward oxidation is sufficient to protect against palmitate-induced lipotoxicity.

show abstract

Glucolipotoxicity in INS-1E cells is counteracted by carnitine palmitoyltransferase 1 over-expression

Cited by 23 publications

References 37 publications

Supplement of TCA cycle intermediates protects against high glucose/palmitate-induced INS-1 beta cell death

Supplement of TCA cycle intermediates protects against high glucose/palmitate-induced INS-1 beta cell death

Modulation of palmitate-induced endoplasmic reticulum stress and apoptosis in pancreatic β-cells by stearoyl-CoA desaturase and Elovl6

Increased Mitochondrial Fatty Acid Oxidation Is Sufficient to Protect Skeletal Muscle Cells from Palmitate-induced Apoptosis

Contact Info

Product

Resources

About