Macrophage-Specific Hypoxia-Inducible Factor-1α Contributes to Impaired Autophagic Flux in Nonalcoholic Steatohepatitis

Xiaojing Wang, Marcelle de Carvalho Ribeiro, Arvin Iracheta-Vellve, Patrick Lowe, Aditya Ambade, Abhishek Satishchandran, Terence Bukong, Donna Catalano, Karen Kodys, G. Szabó

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Inflammatory cell activation drives diverse cellular programming during hepatic diseases. Hypoxia-inducible factors (HIFs) have recently been identified as important regulators of immunity and inflammation. In nonalcoholic steatohepatitis (NASH), HIF-1α is upregulated in hepatocytes, where it induces steatosis; however, the role of HIF-1α in macrophages under metabolic stress has not been explored. In this study, we found increased HIF-1α levels in hepatic macrophages in methionine-choline-deficient (MCD) diet-fed mice and in macrophages of patients with NASH compared with controls. The HIF-1α increase was concomitant with elevated levels of autophagy markers BNIP3, Beclin-1, LC3-II, and p62 in both mouse and human macrophages. LysMCre HIFdPAfl/fl mice, which have HIF-1α levels stabilized in macrophages, showed higher steatosis and liver inflammation compared with HIFdPAfl/fl mice on MCD diet. In vitro and ex vivo experiments reveal that saturated fatty acid, palmitic acid (PA), both induces HIF-1α and impairs autophagic flux in macrophages. Using small interfering RNA–mediated knock-down and overexpression of HIF-1α in macrophages, we demonstrated that PA impairs autophagy via HIF-1α. We found that HIF-1α mediates NF-κB activation and MCP-1 production and that HIF-1α—mediated impairment of macrophage autophagy increases IL-1β production, contributing to MCD diet-induced NASH. Conclusion: Palmitic acid impairs autophagy via HIF-1α activation in macrophages. HIF-1α and impaired autophagy are present in NASH in vivo in mouse macrophages and in human blood monocytes. We identified that HIF-1α activation and decreased autophagic flux stimulate inflammation in macrophages through upregulation of NF-κB activation. These results suggest that macrophage activation in NASH involves a complex interplay between HIF-1α and autophagy as these pathways promote proinflammatory overactivation in MCD diet-induced NASH.

Original languageEnglish
JournalHepatology
DOIs
Publication statusAccepted/In press - Jan 1 2019

Fingerprint

Hypoxia-Inducible Factor 1
Macrophages
Autophagy
Choline
Methionine
Palmitic Acid
Diet
Macrophage Activation
Non-alcoholic Fatty Liver Disease
Inflammation
Physiological Stress
Liver
Fatty Liver
Interleukin-1

ASJC Scopus subject areas

  • Hepatology

Cite this

Wang, X., de Carvalho Ribeiro, M., Iracheta-Vellve, A., Lowe, P., Ambade, A., Satishchandran, A., ... Szabó, G. (Accepted/In press). Macrophage-Specific Hypoxia-Inducible Factor-1α Contributes to Impaired Autophagic Flux in Nonalcoholic Steatohepatitis. Hepatology. https://doi.org/10.1002/hep.30215

Macrophage-Specific Hypoxia-Inducible Factor-1α Contributes to Impaired Autophagic Flux in Nonalcoholic Steatohepatitis. / Wang, Xiaojing; de Carvalho Ribeiro, Marcelle; Iracheta-Vellve, Arvin; Lowe, Patrick; Ambade, Aditya; Satishchandran, Abhishek; Bukong, Terence; Catalano, Donna; Kodys, Karen; Szabó, G.

In: Hepatology, 01.01.2019.

Research output: Contribution to journalArticle

Wang, X, de Carvalho Ribeiro, M, Iracheta-Vellve, A, Lowe, P, Ambade, A, Satishchandran, A, Bukong, T, Catalano, D, Kodys, K & Szabó, G 2019, 'Macrophage-Specific Hypoxia-Inducible Factor-1α Contributes to Impaired Autophagic Flux in Nonalcoholic Steatohepatitis', Hepatology. https://doi.org/10.1002/hep.30215
Wang, Xiaojing ; de Carvalho Ribeiro, Marcelle ; Iracheta-Vellve, Arvin ; Lowe, Patrick ; Ambade, Aditya ; Satishchandran, Abhishek ; Bukong, Terence ; Catalano, Donna ; Kodys, Karen ; Szabó, G. / Macrophage-Specific Hypoxia-Inducible Factor-1α Contributes to Impaired Autophagic Flux in Nonalcoholic Steatohepatitis. In: Hepatology. 2019.
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abstract = "Inflammatory cell activation drives diverse cellular programming during hepatic diseases. Hypoxia-inducible factors (HIFs) have recently been identified as important regulators of immunity and inflammation. In nonalcoholic steatohepatitis (NASH), HIF-1α is upregulated in hepatocytes, where it induces steatosis; however, the role of HIF-1α in macrophages under metabolic stress has not been explored. In this study, we found increased HIF-1α levels in hepatic macrophages in methionine-choline-deficient (MCD) diet-fed mice and in macrophages of patients with NASH compared with controls. The HIF-1α increase was concomitant with elevated levels of autophagy markers BNIP3, Beclin-1, LC3-II, and p62 in both mouse and human macrophages. LysMCre HIFdPAfl/fl mice, which have HIF-1α levels stabilized in macrophages, showed higher steatosis and liver inflammation compared with HIFdPAfl/fl mice on MCD diet. In vitro and ex vivo experiments reveal that saturated fatty acid, palmitic acid (PA), both induces HIF-1α and impairs autophagic flux in macrophages. Using small interfering RNA–mediated knock-down and overexpression of HIF-1α in macrophages, we demonstrated that PA impairs autophagy via HIF-1α. We found that HIF-1α mediates NF-κB activation and MCP-1 production and that HIF-1α—mediated impairment of macrophage autophagy increases IL-1β production, contributing to MCD diet-induced NASH. Conclusion: Palmitic acid impairs autophagy via HIF-1α activation in macrophages. HIF-1α and impaired autophagy are present in NASH in vivo in mouse macrophages and in human blood monocytes. We identified that HIF-1α activation and decreased autophagic flux stimulate inflammation in macrophages through upregulation of NF-κB activation. These results suggest that macrophage activation in NASH involves a complex interplay between HIF-1α and autophagy as these pathways promote proinflammatory overactivation in MCD diet-induced NASH.",
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