title: Hepatic autophagy is suppressed in the presence of insulin resistance and hyperinsulinemia: inhibition of FoxO1-dependent expression of key autophagy genes by insulin.
abstract: Autophagy is essential for maintaining both survival and health of cells. Autophagy is normally suppressed by amino acids and insulin. It is unclear what happens to the autophagy activity in the presence of insulin resistance and hyperinsulinemia. In this study, we examined the autophagy activity in the presence of insulin resistance and hyperinsulinemia and the associated mechanism. Insulin resistance and hyperinsulinemia were induced in mice by a high fat diet, followed by measurements of autophagy markers. Our results show that autophagy was suppressed in the livers of mice with insulin resistance and hyperinsulinemia. Transcript levels of some key autophagy genes were also suppressed in the presence of insulin resistance and hyperinsulinemia. Conversely, autophagy activity was increased in the livers of mice with streptozotocin-induced insulin deficiency. Levels of vps34, atg12, and gabarapl1 transcripts were elevated in the livers of mice with insulin deficiency. To study the mechanism, autophagy was induced by nutrient deprivation or glucagon in cultured hepatocytes in the presence or absence of insulin. Autophagy activity and transcript levels of vps34, atg12, and gabarapl1 genes were reduced by insulin. The effect of insulin was largely prevented by overexpression of the constitutive nuclear form of FoxO1. Importantly, autophagy of mitochondria (mitophagy) in cultured cells was suppressed by insulin in the presence of insulin resistance. Together, our results show that autophagy activity and expression of some key autophagy genes were suppressed in the presence of insulin resistance and hyperinsulinemia. Insulin suppression of autophagy involves FoxO1-mediated transcription of key autophagy genes.
authors.affiliation: Translational Biology, The Hamner Institutes for Health Sciences, Durham, North Carolina 27709, USA.
authors.forename: Hui-Yu
authors.initials: HY
authors.lastname: Liu
authors.forename: Jianmin
authors.initials: J
authors.lastname: Han
authors.forename: Sophia Y
authors.initials: SY
authors.lastname: Cao
authors.forename: Tao
authors.initials: T
authors.lastname: Hong
authors.forename: Degen
authors.initials: D
authors.lastname: Zhuo
authors.forename: Jianbo
authors.initials: J
authors.lastname: Shi
authors.forename: Zhenqi
authors.initials: Z
authors.lastname: Liu
authors.forename: Wenhong
authors.initials: W
authors.lastname: Cao
mesh_terms: D000818:Animals; D001343:Autophagy; D002478:Cells, Cultured; D004195:Disease Models, Animal; D015536:Down-Regulation; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism; D006801:Humans; D006946:Hyperinsulinism / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D007328:Insulin / Q000235:genetics / Q000378:metabolism*; D007333:Insulin Resistance; D008099:Liver / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL
chemical_list: D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D007328:Insulin