Stimulation of autophagy in the liver by lipopolysaccharide-induced systemic inflammation in a rat model of diabetes mellitus

Hagiwara, Satoshi; Iwasaka, Hideo; Koga, Hironori; Hasegawa, Akira; Kudo, Kazuhiro; Kusaka, Jyunya; Oyama, Yoshimasa; Noguchi, Takayuki

doi:10.2220/biomedres.31.263

Cited by 16 publications

(12 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Many studies support this LPS toxicity [44-48]. However, Aβ42, which induced a low grade of inflammation, inhibited the activation of the mTOR pathway and could activate autophagy.…”

Section: Discussionmentioning

confidence: 99%

Involvement of interleukin-1β in the autophagic process of microglia: relevance to Alzheimer’s disease

Audigier

Terro

Janet

et al. 2013

J Neuroinflammation

View full text Add to dashboard Cite

BackgroundAutophagy is a major pathway of protein and organelle degradation in the lysosome. Autophagy exists at basal constitutive level and can be induced as a defense mechanism under stress conditions. Molecular relationships between autophagy and inflammation at the periphery were recently evidenced, highlighting a role of autophagy in the regulation of inflammation. Impairment of autophagy (with accumulation of autophagic vacuoles) and substantial inflammation are found in neurodegenerative diseases such as Alzheimer’s Disease (AD). However, the links between autophagy and inflammation in AD remain to be determined.MethodsHere, we examined the inflammatory reaction and autophagy in murine tri-cultures of neurons, astrocytes, and microglia. Tri-cultures were exposed to various inflammatory stresses (lipopolysaccharide (LPS), amyloid peptide (Aβ42) with or without cytokines) for 48 hours. Furthermore, the relationships between inflammation and autophagy were also analyzed in astrocyte- and microglia-enriched cultures. Data for multiple variable comparisons were analyzed by a one-way ANOVA followed by a Newman-keuls’ test.ResultsAβ42 induced a low inflammation without accumulation of acidic vesicles contrary to moderate or severe inflammation induced by LPS or the cytokine cocktail (IL-1β, TNF-α, and IL-6) or IL-1β alone which led to co-localization of p62 and LC3, two markers of autophagy, with acidic vesicles stained with Lyso-ID Red dye. Moreover, the study reveals a major role of IL-1β in the induction of autophagy in tri-cultures in the presence or absence of Aβ42. However, the vulnerability of the autophagic process in purified microglia to IL-1β was prevented by Aβ42.ConclusionThese findings show a close relationship between inflammation and autophagy, in particular a major role of IL-1β in the induction of the microglial autophagy which could be the case in AD. New therapeutic strategies could target inflammasome and autophagy in microglia to maintain its role in the amyloid immunosurveillance.

show abstract

“…Many studies support this LPS toxicity [44-48]. However, Aβ42, which induced a low grade of inflammation, inhibited the activation of the mTOR pathway and could activate autophagy.…”

Section: Discussionmentioning

confidence: 99%

Involvement of interleukin-1β in the autophagic process of microglia: relevance to Alzheimer’s disease

Audigier

Terro

Janet

et al. 2013

J Neuroinflammation

View full text Add to dashboard Cite

show abstract

“…32,33 However, the functional role of autophagy in other diabetic organs remains unknown. For example, in streptozotocin-diabetic rats, autophagy appears to be increased in the liver, 34,35 but reduced in the kidney. 36,37 In the OVE26 type 1 diabetic mouse heart, autophagy is inhibited, which is associated with cardiac dysfunction.…”

Section: Introductionmentioning

confidence: 99%

Suppression of autophagy is protective in high glucose-induced cardiomyocyte injury

Kobayashi

Chen³

et al. 2012

Autophagy

132

View full text Add to dashboard Cite

Abbreviations: DMEM, Dulbecco's modified essential medium; 3-MA, 3-methyladenine; BAF, bafilomycin A 1 ; GFP, green fluorescent protein; AVs, autophagic vacuoles; LC3, microtubule-associated protein 1 light chain 3; mRFP, monomeric red fluorescent protein; mTOR, mammalian target of rapamycin; mTORC1, mTOR complex 1; BECN1, Beclin 1; ULK1, unc-51-like kinase 1; PI, propidium iodide; Rap, rapamycin; AMPK, AMP-activated protein kinase; ACC, acetyl-CoA carboxylase; S6K, p70 ribosomal protein S6 kinase; 4EBP, elongation factor 4E binding protein; PARP, Poly (ADP-ribose) polymerase; shRNA, short hairpin RNA; β-gal, β-galactosidaseHyperglycemia is linked to increased heart failure among diabetic patients. However, the mechanisms that mediate hyperglycemia-induced cardiac damage remain poorly understood. Autophagy is a cellular degradation pathway that plays important roles in cellular homeostasis. Autophagic activity is altered in the diabetic heart, but its functional role has been unclear. In this study, we determined if mimicking hyperglycemia in cultured cardiomyocytes from neonatal rats and adult mice could affect autophagic activity and myocyte viability. High glucose (17 or 30 mM) reduced autophagic flux compared with normal glucose (5.5 mM) as indicated by the difference in protein levels of LC3-II (microtubule-associated protein 1 light chain 3 form II) or the changes of punctate fluorescence patterns of GFP-LC3 and mRFP-LC3 in the absence and presence of the lysosomal inhibitor bafilomycin A 1 . Unexpectedly, the inhibited autophagy turned out to be an adaptive response that functioned to limit high glucose cardiotoxicity. Indeed, suppression of autophagy by 3-methyladenine or short hairpin RNA-mediated silencing of the Becn1 or Atg7 gene attenuated high glucose-induced cardiomyocyte death. Conversely, upregulation of autophagy with rapamycin or overexpression of Becn1 or Atg7 predisposed cardiomyocytes to high glucose toxicity. Mechanistically, the high glucose-induced inhibition of autophagy was mediated at least partly by increased mTOR signaling that likely inactivated ULK1 through phosphorylation at serine 467. Together, these findings demonstrate that high glucose inhibits autophagy, which is a beneficial adaptive response that protects cardiomyocytes against high glucose toxicity. Future studies are warranted to determine if autophagy plays a similar role in diabetic heart in vivo.

show abstract

“…Extensive liver autophagy results in non-selective catabolization of cytoplasmic components into amino acids and free fatty acids, which are used in gluconeogenesis and beta-oxidation (Komatsu 2012). Usually, autophagy is considered as a protective mechanism, but hyperactive autophagy has also been reported in pathological conditions such as liver inflammation in a rat model of diabetes mellitus (Hagiwara et al 2010) and as a possible cause of hepatocyte death in anorexia nervosa patients (Rautou et al 2008) suggesting that both diminished or excessive autophagy could be deleterious. It has also been reported that leptin treatment might have unfavorable consequences via an overactivated leptin system and an SOCS3 inhibitory effect might lead to insulin resistance, hepatic steatosis and liver fibrosis (Polyzos et al 2011).…”

Section: Discussionmentioning

confidence: 99%

Long-term fructose feeding changes the expression of leptin receptors and autophagy genes in the adipose tissue and liver of male rats: a possible link to elevated triglycerides

et al. 2013

View full text Add to dashboard Cite

Long-term fructose consumption has been shown to evoke leptin resistance, to elevate triglyceride levels and to induce insulin resistance and hepatic steatosis. Autophagy has been suggested to function in processes such as lipid storage in adipose tissue and inflammation in liver. Autophagy and the leptin system have also been suggested to regulate each other. This study aimed to identify the changes caused by fetal undernourishment and postnatal fructose diet in the gene expression of leptin, its receptors (LEPR-a, LEPR-b, LEPR-c, LEPR-e and LEPR-f) and autophagy genes in the white adipose tissue (WAT) and liver of adult male rats in order to clarify the mechanism behind the metabolic alterations. The data clearly revealed that the long-term postnatal fructose diet decreased leptin levels (p < 0.001), LEPR (p < 0.001), especially LEPR-b (p = 0.011) and LEPR-f (p = 0.005), as well as SOCS3 (p < 0.001), ACC (p = 0.006), ATG7 (p < 0.001), MAP1LC3β (p < 0.001) and LAMP2 (p = 0.004) mRNA expression in WAT. Furthermore, LEPR (p < 0.001), especially LEPR-b (p = 0.001) and LEPR-f (p < 0.001), ACC (p = 0.010), ATG7 (p = 0.024), MAP1LC3β (p = 0.003) and LAMP2 (p < 0.001) mRNA expression in the liver was increased in fructose-fed rats. In addition, the LEPR expression in liver and MAP1LC3β expression in WAT together explained 55.7 % of the variation in the plasma triglyceride levels of the rats (R adj. (2) = 0.557, p < 0.001). These results, together with increased p62 levels in WAT (p < 0.001), could indicate decreased adipose tissue lipid storing capacity as well as alterations in liver metabolism which may represent a plausible mechanism through which fructose consumption could disturb lipid metabolism and result in elevated triglyceride levels.

show abstract

Stimulation of autophagy in the liver by lipopolysaccharide-induced systemic inflammation in a rat model of diabetes mellitus

Cited by 16 publications

References 33 publications

Involvement of interleukin-1β in the autophagic process of microglia: relevance to Alzheimer’s disease

Involvement of interleukin-1β in the autophagic process of microglia: relevance to Alzheimer’s disease

Suppression of autophagy is protective in high glucose-induced cardiomyocyte injury

Long-term fructose feeding changes the expression of leptin receptors and autophagy genes in the adipose tissue and liver of male rats: a possible link to elevated triglycerides

Contact Info

Product

Resources

About