Bip overexpression, but not CHOP inhibition, attenuates fatty-acid-induced endoplasmic reticulum stress and apoptosis in HepG2 liver cells

Gu, Xin; Li, Kwan; Laybutt, D. Ross; He, Ming; Zhao, Hai-Lu; Chan, Juliana C.N.; Xu, Gang

doi:10.1016/j.lfs.2010.10.012

Cited by 54 publications

(43 citation statements)

References 29 publications

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“…Their lipid sensitivity was retained when the luminal unfolded protein sensing domains were removed and was associated to their transmembrane domains [71] . This novel mechanism is in accordance with the greater toxicity of saturated vs unsaturated fatty acids as well as with the protective effect of unsaturated fatty acids against saturated fatty acid induced toxicity [18,[22][23][24][25] . The thapsigargin-and tunicamycin-induced UPR was found to increase the expression of sterol regulatory element-binding protein (SREBP-1c) transcription factor in HepG2 cells, through the cap-independent translation mediated by an internal ribosome entry site [72] .…”

Section: Lipotoxic Er Stresssupporting

confidence: 72%

“…Elevated exogenous pamitate has been shown to disrupt ER homeostasis by reducing the expression of Bip in HepG2 cells. Overexpression of Bip attenuated ER stress, reduced CHOP expression and protected the cells from palmitate-induced apoptosis [22] . Lipotoxic derangement of ER functions is likely due to the above mentioned oxidative stress, disturbed calcium homeostasis and altered membrane saturation.…”

Section: Lipotoxic Er Stressmentioning

confidence: 98%

“…Hindrance of protective fat synthesis favors fatty acid oxidation and leads to excessive ROS generation; The emerging oxidative stress and the increased saturation of membrane lipids trigger the endoplasmic reticulum (ER) stress response, which contributes to insulin resistance and further enhances cell death (dotted lines). The greater hepatotoxicity of saturated vs unsaturated fatty acids has been demonstrated in several studies [18,[22][23][24][25] . Moreover, the unsaturated fatty acids often prove to be protective against SFA-induced toxicity [18,24] .…”

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confidence: 96%

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Lipotoxicity in the liver

Zámbó

Simon-Szabó

Szelényi

et al. 2013

WJH

164

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Obesity due to excessive food intake and the lack of physical activity is becoming one of the most serious public health problems of the 21 st century. With the increasing prevalence of obesity, non-alcoholic fatty liver disease is also emerging as a pandemic. While previously this pathophysiological condition was mainly attributed to triglyceride accumulation in hepatocytes, recent data show that the development of oxidative stress, lipid peroxidation, cell death, inflammation and fibrosis are mostly due to accumulation of fatty acids, and the altered composition of membrane phospholipids. In fact, triglyceride accumulation might play a protective role, and the higher toxicity of saturated or trans fatty acids seems to be the consequence of a blockade in triglyceride synthesis. Increased membrane saturation can profoundly disturb cellular homeostasis by impairing the function of membrane receptors, channels and transporters. However, it also induces endoplasmic reticulum stress via novel sensing mechanisms of the organelle's stress receptors. The triggered signaling pathways in turn largely contribute to the development of insulin resistance and apoptosis. These findings have substantiated the lipotoxic liver injury hypothesis for the pathomechanism of hepatosteatosis. This minireview focuses on the metabolic and redox aspects of lipotoxicity and lipoapoptosis, with special regards on the involvement of endoplasmic reticulum stress responses. Key words: Saturated fatty acid; Lipotoxicity; Steatosis; Lipoapoptosis; Endoplasmic reticulum stress Core tip: Surplus of free fatty acids contributes to hepatic injuries in obesity and type 2 diabetes. Intracellular accumulation of fatty acyl-CoA causes oxidative and endoplasmic reticulum (ER) stress, which lead to cell death, inflammation and fibrosis. Steatohepatosis is the consequence of an intensive fat synthesis, aiming to reduce the metabolic burden. The higher toxicity of saturated vs unsaturated fatty acids is partly due to a limited capacity of the liver cells to insert them into triglycerides. Moreover, increased membrane saturation triggers the ER stress response though a unique mechanism, which aggravates the metabolic derangements and liver injuries.

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Section: Lipotoxic Er Stresssupporting

confidence: 72%

Section: Lipotoxic Er Stressmentioning

confidence: 98%

mentioning

confidence: 96%

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Lipotoxicity in the liver

Zámbó

Simon-Szabó

Szelényi

et al. 2013

WJH

164

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“…Though we and others have demonstrated OA-induced ER stress ( 6,36 ), this has not been a universal observation ( 37,38 ). Furthermore, the mechanism for OA-induced periods, induced ER stress and decreased the secretion of apoB100 ( 6 ).…”

Section: Dha But Not Oa or Pa Increases Autophagic Fl Ux In Mca Cellsmentioning

confidence: 72%

Different fatty acids inhibit apoB100 secretion by different pathways: unique roles for ER stress, ceramide, and autophagy

Caviglia

Gayet

Ota

et al. 2011

Journal of Lipid Research

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“…Consistently, knock-down of PERK significantly reduced palmitateinduced cell death (91). Attenuation of ER stress by BiP overexpression (92), by resveratrol treatment (93), glucagonlike peptide-1 (GLP-1) treatment (94), or TLR4 knockout (95) suppressed palmitate-induced cell death. In addition, palmitate-induced hepatocyte death was attenuated by miR-615-3p, which suppressed the expression of the apoptotic gene, CHOP (96).…”

Section: Er Stress and Lipotoxicity In Peripheral Organsmentioning

confidence: 86%

The role of ER stress in lipid metabolism and lipotoxicity

Han

Kaufman

2016

Journal of Lipid Research

504

372

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extremely high Ca 2+ concentration (1), which is maintained by the active transport function of the sarco/ER calcium ATPase (SERCA) (2). Many ER chaperone proteins and enzymes depend on higher Ca 2+ levels to facilitate protein folding and maturation (3). Therefore, maintaining ER homeostasis is essential for proper protein production and cell function. Homeostasis in the ER is disrupted by a number of insults, including pharmacological perturbation, genetic mutation of ER chaperones or their client proteins, elevated expression of proteins that transit the endomembrane system, viral infection, alterations in Ca 2+ or redox status, and limited or excessive available nutrients such as lipids. The accumulation of unfolded or misfolded proteins in the ER lumen activates a set of intracellular signaling pathways known as the unfolded protein response (UPR) (4, 5). The UPR regulates the quantity of ER driven by synthesis of lipids (6) and protein components of the ER to accommodate fluctuating demands on protein folding and other ER functions in response to different physiological and pathological conditions.The ER is also the major site for the synthesis of sterols and phospholipids that constitute the bulk of the lipid components of all biological membranes. In addition, many enzymes and regulatory proteins involved in lipid metabolism reside in the ER. The ER, therefore, plays an essential role in controlling membrane lipid composition (7) and membrane lipid homeostasis in all cell types. Fat The endoplasmic reticulum (ER) is a central organelle where proteins destined for the cell surface and the endomembrane system enter the secretory pathway. Once inside the ER lumen, newly synthesized polypeptides fold into their three-dimensional structures, assemble into higher order multimeric complexes, and are subject to posttranslational modifications such as glycosylation, hydroxylation, lipidation, and disulfide formation. The ER contains an Abbreviations: ACC, acetyl-CoA carboxylase; ATF4, activating transcription factor 4; ATF6, activating transcription factor 6; BiP, immunoglobulin heavy-chain binding protein; CHOP, C/EBP homologous protein; eIF2, eukaryotic translation initiation factor 2; ER, endoplasmic reticulum; ERAD, ER-associated degradation; FXR, farnesoid X receptor; GADD34, growth arrest and DNA damage-inducible protein 34; HFD, high-fat diet; HFrD, high-fructose diet; IRE1, inositol-requiring enzyme 1; 4-PBA, 4-phenylbutyric acid; PERK, the double-stranded RNAactivated protein kinase-like eukaryotic initiation factor 2 kinase; ROS, reactive oxygen species; SCD1, stearoyl-CoA desaturase 1; SERCA, sarco/ endoplasmic reticulum calcium ATPase; SFA, saturated fatty acid; S1P, serine protease site-1; S2P, metalloprotease site-2; SREBP, sterol regulatory element-binding protein; TUDCA, tauroursodeoxycholic acid; UPR, unfolded protein response; VLDLR, VLDL receptor; XBP1, X-box binding protein 1; Xbp1s, transcriptionally active form of X-box binding protein 1.

show abstract

Bip overexpression, but not CHOP inhibition, attenuates fatty-acid-induced endoplasmic reticulum stress and apoptosis in HepG2 liver cells

Cited by 54 publications

References 29 publications

Lipotoxicity in the liver

Lipotoxicity in the liver

Different fatty acids inhibit apoB100 secretion by different pathways: unique roles for ER stress, ceramide, and autophagy

The role of ER stress in lipid metabolism and lipotoxicity

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