Defective Hepatic Autophagy in Obesity Promotes ER Stress and Causes Insulin Resistance

By Ling Yang, Ping Li, Suneng Fu, Ediz S. Calay, G. Hotamışlıgil. Cell Metabolism, 2010

1,254 citations recorded by the source corpus.

SUMMARY Autophagy is a homeostatic process involved in the bulk degradation of cytoplasmic components including damaged organelles and proteins. In both genetic and dietary models of obesity, we observed a severe downregulation of autophagy, particularly in Atg7 expression levels in liver. Suppression of Atg7 both in vitro and in vivo resulted in defective insulin signaling and elevated ER stress. In contrast, restoration of the Atg7 expression in liver resulted in dampened ER stress, enhanced hepatic insulin action and systemic glucose tolerance in obese mice. The beneficial action of Atg7 restoration in obese mice could be completely prevented by blocking a downstream mediator, Atg5, supporting its dependence on autophagy in regulating insulin action. Our data demonstrate that autophagy is an important regulator of organelle function and insulin signaling and loss of autophagy is a critical component of defective insulin action seen in obesity.

Subfields: Cell Biology, Epidemiology, Surgery

View Paper: https://www.semanticscholar.org/paper/1557147c6e241427357408c35ca13c89e1c6d55d

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Citations in the corpus

Mechanisms and disease consequences of nonalcoholic fatty liver disease (2021, background): “, 2014) and obesity (Yang et al., 2010), whichmay contribute to lipid accumulation in liver and adipose tissue.”
Measuring in vivo mitophagy (2015, background): “Previous observations have demonstrated that overall hepatic autophagic flux is reduced following chronic high fat feeding (Papá cková et al., 2012; Yang et al., 2010).”
Autophagy in the Cellular Energetic Balance (2011, neutral): “In fact, dietary and genetic models of obesity (ob/ob mouse) display markedly reduced macroautophagy in liver that alters insulin signaling in these models (Yang et al., 2010).”
Endoplasmic reticulum stress signalling and the pathogenesis of non-alcoholic fatty liver disease. (2018, background): “Interestingly, PERK and IRE1α were upregulated in livers of ob/ob models(81).”
The interaction of hepatic lipid and glucose metabolism in liver diseases. (2012, background): “Thus, disrupted autophagy might be essential to the pathogenesis of NASH via lipotoxicity-induced ER stress [12].”
PAMPs and DAMPs: Signal 0s that Spur Autophagy and Immunity (2012, background): “Autophagy is involved in other inflammatory disorders including cystic fibrosis (150), obesity (151), and sepsis (152).”
Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition) (2012, neutral): “With regard to ATG5, a better approach may be to use a dominant negative (K130R) version.(1144,1198,1210) Also noteworthy is the role of ATG5 in mitotic catastrophe(544) and several other nonautophagic roles of ATG proteins (see Noncanonical use of autophagy-related proteins).”
Evolution of inflammation in nonalcoholic fatty liver disease: The multiple parallel hits hypothesis (2010, background): “Autophagy seems to critically interact with ER stress because impaired hepatic autophagy results in elevated ER stress and defective insulin signaling.(96) Therefore, ER stress and autophagy appear as closely intertwined pathways in inflammatory diseases.”