2. Academic Validation
  3. ETNPPL impairs autophagy through regulation of the ARG2-ROS signaling axis, contributing to palmitic acid-induced hepatic insulin resistance

ETNPPL impairs autophagy through regulation of the ARG2-ROS signaling axis, contributing to palmitic acid-induced hepatic insulin resistance

  • Free Radic Biol Med. 2023 Feb 23;S0891-5849(23)00090-4. doi: 10.1016/j.freeradbiomed.2023.02.017.
Caihua Wang 1,  Xiaofang Li 2,  Wei Zhang 3,  Wenxuan Liu 1,  Ziwei Lv 1,  Runlin Gui 1,  Man Li 3,  Li Yujia 3,  Sun Xiaomin 3,  Ping Liu 3,  Xiaobin Fan 4,  Shiyao Yang 1,  Yuyan Xiong 5,  Lu Qian 6
Affiliations

Affiliations

  • 1 Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Faculty of Life Sciences and Medicine, Xi'an No.3 Hospital, The Affiliated Hospital of Northwest University, Northwest University, Xi'an, Shaanxi, 710069, PR China; Xi'an Key Laboratory of Cardiovascular and Cerebrovascular Diseases, Xi'an No.3 Hospital, The Affiliated Hospital of Northwest University, Northwest University, Xi'an, Shaanxi, 710018, PR China.
  • 2 Department of Gastroenterology, Xi'an No.3 Hospital, The Affiliated Hospital of Northwest University, Northwest University, Xi'an, Shaanxi, 710018, PR China.
  • 3 Department of Endocrinology, Xi'an No.3 Hospital, The Affiliated Hospital of Northwest University, Northwest University, Xi'an, Shaanxi, 710018, PR China.
  • 4 Department of Obstetrics and Gynecology, Xi'an No.3 Hospital, The Affiliated Hospital of Northwest University, Northwest University, Xi'an, Shaanxi, 710018, PR China.
  • 5 Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Faculty of Life Sciences and Medicine, Xi'an No.3 Hospital, The Affiliated Hospital of Northwest University, Northwest University, Xi'an, Shaanxi, 710069, PR China; Xi'an Key Laboratory of Cardiovascular and Cerebrovascular Diseases, Xi'an No.3 Hospital, The Affiliated Hospital of Northwest University, Northwest University, Xi'an, Shaanxi, 710018, PR China. Electronic address: [email protected].
  • 6 Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Faculty of Life Sciences and Medicine, Xi'an No.3 Hospital, The Affiliated Hospital of Northwest University, Northwest University, Xi'an, Shaanxi, 710069, PR China; Department of Endocrinology, Xi'an No.3 Hospital, The Affiliated Hospital of Northwest University, Northwest University, Xi'an, Shaanxi, 710018, PR China; Xi'an Key Laboratory of Cardiovascular and Cerebrovascular Diseases, Xi'an No.3 Hospital, The Affiliated Hospital of Northwest University, Northwest University, Xi'an, Shaanxi, 710018, PR China. Electronic address: [email protected].
PMID: 36841363 DOI: 10.1016/j.freeradbiomed.2023.02.017
Abstract

Excessive free fatty acids (FFAs) accumulation is a leading risk factor for the pathogenesis of Insulin resistance (IR) in metabolic tissues, including the liver. Ethanolamine-phosphate phospho-lyase (ETNPPL), a newly identified metabolic Enzyme, catalyzes phosphoethanolamine (PEA) to ammonia, inorganic phosphate, and acetaldehyde and is highly expressed in hepatic tissue. Whether it plays a role in regulating FFA-induced IR in hepatocytes has yet to be understood. In this study, we established an in vitro palmitic acid (PA)-induced IR model in human HepG2 cells and mouse AML12 cells with chronic treatment of PA. Next, we overexpressed ETNPPL by using lentivirus-mediated ectopic to investigate the effects of ETNPPL per se on IR without PA stimulation. We show that ETNPPL expression is significantly elevated in PA-induced IR and that silencing ETNPPL ameliorates this IR in hepatocytes. Inversely, overexpressing ETNPPL under normal conditions without PA promotes IR, Reactive Oxygen Species generation, and ARG2 activation in both HepG2 and AML12 cells. Moreover, ETNPPL depletion markedly down-regulates ARG2 expression in hepatocytes. Besides, silencing ARG2 prevents ETNPPL-induced ROS accumulation and inhibition of autophagic flux and IR in hepatocytes. Finally, we found that phytopharmaceutical disruption of ETNPPL by quercetin ameliorates PA-induced IR in hepatocytes. Our study discloses that ETNPPL inhibiting autophagic flux mediates Insulin resistance triggered by PA in hepatocytes via ARG2/ROS signaling cascade. Our findings provide novel insights into elucidating the pathogenesis of obesity-associated hepatic IR, suggesting that targeting ETNPPL might represent a potential approach for T2DM therapy.

Keywords

ARG2; Autophagic flux; ETNPPL; Insulin resistance; Palmitic acid; ROS.

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