Regulation of apoptosis by free fatty acids and Tnf-α: Role of double-stranded RNA-dependent protein kinase (Pkr)

Xuerui Yang, Zheng Li, Shireesh Srivastava, Christina Chan

Research output: Chapter in Book/Report/Conference proceedingConference contribution

Abstract

Different types of free fatty acids (FFAs) have distinct roles in cellular apoptosis: saturated FFAs (e.g. palmitate) have been found to induce apoptosis, while unsaturated FFAs (e.g. oleate) have been found to protect cells from apoptosis induced by other factors such as saturated FFAs (1,2). Saturated FFA-induced apoptosis has been found to be dependent on the Bcl-2 level (3) and transcription factor, NF-κB, activity (4). Physiologically, high levels of proinflammatory cytokine, tumour necrosis factor α (TNF-α), and saturated FFAs usually appear simultaneously in numerous diseases, such as obesity and diabetes (5, 6). TNF-α has been reported to induce apoptosis by various mechanisms, including down-regulating Bcl-2 protein expression level (7), dephosphorylating Bcl-2 at Ser 87 residue (8), activating NF-κB (3), and phosphorylating eukaryotic initiation factor (eIF2) α (9). Upon auto-phosphorylation and dimerization, PKR, a serine/threonine kinase, is activated and highly involved in phosphorylating eIF2-α (10), activating NF-κB through I-κB kinase complex (IKK) (11), and stimulating protein phosphatase 2A (PP2A) (12), which in turn dephosphorylates Bcl-2 at both serine 70 and 87 residues (13, 14). Given the regulatory roles of PKR in activating NF-κB and phosphorylating Bcl-2 and eIF2-α, we hypothesize that PKR is involved in mediating FFA- and TNF-α-induced apoptosis. TNF-α-induced PKR activation has been observed in several systems such as articular chondrocytes and U937 cells (15-17), however in our in vitro system (HepG2/C3A cell line), TNF-α was found to decrease the phosphorylation of PKR in both control and palmitate cultures. Saturated FFA (palmitate) also decreased the phosphorylation of PKR while unsaturated FFA (oleate) had no effect on PKR phosphorylation. By inhibiting PKR activity, we found that PKR is required for maintaining the level of Bcl-2 in HepG2/C3A cells. We proposed that PKR is involved in the signaling from FFAs and TNF-α to Bcl-2. In addition, we studied the role of PKR in mediating the phosphorylation of Bcl-2 and eIF-2α, which help transduce the apoptotic signals initiated by FFAs and TNF-α. Our findings suggest a role of PKR in FFA- and TNF-α-induced apoptosis, mediated through the protein level and phosphorylation status of Bcl-2 and eIF-2α.

Original languageEnglish (US)
Title of host publicationAIChE Annual Meeting, Conference Proceedings
Pages8915-8916
Number of pages2
StatePublished - 2005
Externally publishedYes
Event05AIChE: 2005 AIChE Annual Meeting and Fall Showcase - Cincinnati, OH, United States

Other

Other05AIChE: 2005 AIChE Annual Meeting and Fall Showcase
CountryUnited States
CityCincinnati, OH
Period10/30/0511/4/05

Profile

Fatty acids
Cell death
Phosphorylation
Proteins
Transcription factors
Dimerization
Phosphatases
Medical problems
RNA
Chemical activation
Cells

ASJC Scopus subject areas

  • Engineering(all)

Cite this

Yang, X., Li, Z., Srivastava, S., & Chan, C. (2005). Regulation of apoptosis by free fatty acids and Tnf-α: Role of double-stranded RNA-dependent protein kinase (Pkr). In AIChE Annual Meeting, Conference Proceedings (pp. 8915-8916)

Regulation of apoptosis by free fatty acids and Tnf-α : Role of double-stranded RNA-dependent protein kinase (Pkr). / Yang, Xuerui; Li, Zheng; Srivastava, Shireesh; Chan, Christina.

AIChE Annual Meeting, Conference Proceedings. 2005. p. 8915-8916.

Research output: Chapter in Book/Report/Conference proceedingConference contribution

Yang, X, Li, Z, Srivastava, S & Chan, C 2005, Regulation of apoptosis by free fatty acids and Tnf-α: Role of double-stranded RNA-dependent protein kinase (Pkr). in AIChE Annual Meeting, Conference Proceedings. pp. 8915-8916, 05AIChE: 2005 AIChE Annual Meeting and Fall Showcase, Cincinnati, OH, United States, 30-4 November.
Yang X, Li Z, Srivastava S, Chan C. Regulation of apoptosis by free fatty acids and Tnf-α: Role of double-stranded RNA-dependent protein kinase (Pkr). In AIChE Annual Meeting, Conference Proceedings. 2005. p. 8915-8916.

Yang, Xuerui; Li, Zheng; Srivastava, Shireesh; Chan, Christina / Regulation of apoptosis by free fatty acids and Tnf-α : Role of double-stranded RNA-dependent protein kinase (Pkr).

AIChE Annual Meeting, Conference Proceedings. 2005. p. 8915-8916.

Research output: Chapter in Book/Report/Conference proceedingConference contribution

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