Dihydroartemisinin attenuates alcoholic fatty liver through regulation of lipin‐1 signaling

Abstract

Alcoholic liver disease (ALD) is generated from excessive alcohol consumption, characterized by hepatic steatosis. Mechanistically, excessive hepatic lipid accumulation was attributed to the aberrant lipin-1 signaling during the development of alcoholic steatosis in rodent species and human. Dihydroartemisinin (DHA) has been recently identified to relieve hepatocytes necrosis and prevent from hepatic steatosis in alcohol-induced liver diseases; however, the role of DHA in ALD has not been elucidated completely. Therefore, this study was aimed to further identify the potential mechanisms of pharmacological effects of DHA on ALD. Results demonstrated that DHA regulated the expression and nucleocytoplasmic shuttling of lipin-1 in mice with chronic ethanol exposure. Results confirmed that the disruption of lipin-1 signaling abolished the suppression of DHA on alcohol-induced hepatic steatosis. Interestingly, DHA also significantly improved liver injury, and inflammation mediated by lipin-1 signaling in chronic alcohol-fed mice. in vivo experiments further consolidated the concept that DHA protected against hepatocyte lipoapoptosis dependent on the regulation of nucleocytoplasmic shuttling of lipin-1 signaling, resulting in attenuated ratio of Lpin1 β/α. Obvious increases in cell apoptosis were observed in alcohol-treated lipin1β-overexpressed mice. Although DHA attenuated cell apoptosis, overexpression of lipin-1β neutralized DHA action. DHA ameliorated activation of endoplasmic reticulum stress through inhibiting activation of JNK and CHOP, which was abrogated by overexpression of lipin-1β. In summary, DHA significantly improved liver injury, steatosis and hepatocyte lipoapoptosis in chronic alcohol-fed mice via regulation of lipin-1 signaling.Abbreviations: ALD, alcoholic liver disease; ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aminotransferase; Bax, bcl-associated X protein; Bcl-2, b-cell lymphoma-2; Bim, bcl-2-like protein 11; CHOP, C/EBP homologous protein; CPT1, carnitine palmitoyltransferase 1; DHA, dihydroartemisinin; DMEM, Dulbecco's modified eagle medium; DMSO, dimethylsulfoxide; EIF2α, eukaryotic translation initiation factor-2α; ER, endoplasmic reticulum; FAS, fatty acid synthase; FBS, fetal bovine serum; H&E, hematoxylin-eosin; HSC, hepatic stellate cell; IL-6, interleukin-6; IL-8, interleukin-8.; IRE1, inositol requiring enzyme 1; JNK, c-Jun N-terminal kinase; LDH, alkaline phosphatase; PERK, protein kinase R-like endoplasmic reticulum kinase; PGC1α, peroxisome proliferator-activated receptor gamma coactivator-1α; PPARα, peroxisome proliferator-activated receptor α; PUMA, p53-upregulated modulator of apoptosis; SCD1, stearoyl-CoA desaturase-1; SREBP-1c, sterol regulatory element-binding protein-1c; TC, total cholesterol; TG, triglyceride; TNF-α, tumor necrosis factor α; TUNEL, terminal deoxynucleotidyl transferasemediated deoxyuridine triphosphate nick-end labeling.Xingran Chen and Mianli Bian contributed equally to this study.

The AMPK pathway in fatty liver disease

“…Lipin-1 is further divided into two protein subtypes in liver tissue, lipin-1α and lipin-1β. Lipin-1α is primarily distributed in the nucleus of hepatocytes and promotes the expression of fatty acid oxidation genes, whereas lipin-1β is primarily distributed in the cytoplasm and promotes the expression of fatty acid synthesis genes ( Hu et al, 2013 ; Chen et al, 2019b ). Chen et al investigated whether dihydroartemisinin alleviated AFLD by regulating lipin-1 signaling pathway ( Chen et al, 2019b ).…”

Anti-malarial drug: the emerging role of artemisinin and its derivatives in liver disease treatment

“…DHA attenuated alcohol-induced lipid accumulation in mouse livers by suppressing stearoyl-CoA-desaturase 1 (SCD1), Fas, and SREBP-1c, while increasing the expression of PPAR-α and carnitine palmitoyltransferase 1A (CPT-1A), the regulator of fatty acid oxidation [ 122 ]. Additionally, a previous study reported that DHA regulated nucleocytoplasmic shuttling of lipin-1 to alleviate alcohol-induced liver impairment in mice [ 123 ].…”

Iron Promotes Dihydroartemisinin Cytotoxicity via ROS Production and Blockade of Autophagic Flux via Lysosomal Damage in Osteosarcoma

“…The antimalarial and antiproliferative drug dihydroartemisinin (DHA), derived from artemisinin, has been reported to function by interacting with free iron in the food vacuole of the malaria parasite, leading to damage of the vacuole through lethal ROS generation (Antoine et al, 2014;Dalal and Klemba, 2015). In addition to antimalarial effects, DHA has been found to also exhibit actions against cancer (Mao et al, 2013;Qin et al, 2015;Zou et al, 2019), inflammatory bowel disease (Yan et al, 2019), alcoholic fatty liver (Chen et al, 2019), osteoarthritic synovium (Li D. et al, 2019), lipopolysaccharide-induced osteoclastogenesis and bone loss (Dou et al, 2016), liver fibrosis (Zhang et al, 2017), and systemic lupus erythematosus . Especially, DHA effectively inhibits cancer cell proliferation in vitro and in vivo (Liao et al, 2014).…”