Waqar Khalid Saeed1, Dae Won Jun1,2, Kiseok Jang3, Ju Hee Oh2, Yeon Ji Chae2, Jai Sun Lee2, Dong Hee Koh4, Hyeon Tae Kang2. 1. Department of Internal Medicine, Hanyang University College of Medicine, Seoul, South Korea. 2. Department of Translational Medicine, Hanyang University Graduate School of Biomedical Science and Engineering, Seoul, South Korea. 3. Department of Pathology, Hanyang University College of Medicine, Seoul, South Korea. 4. Department of Internal Medicine, Hallym University Dongtan Sacred Heart Hospital, Hwaseong-si, South Korea.
Abstract
BACKGROUND AND AIM: Receptor-interacting serine/threonine kinase 3 and mixed lineage kinase domain-like pseudokinase (MLKL) have gained attention as apoptosis alternate cell death signaling molecules. We aimed to evaluate the role of MLKL in non-alcoholic fatty liver disease (NAFLD). METHODS: Hepatic tissue MLKL expression was compared between NAFLD patients and healthy controls. High-fat diet was fed to wild-type and MLKL-knockout (KO) mice for 12 weeks. Brown adipose fat tissue was measured by [18 F]-fluorodeoxyglucose positron emission tomography. Energy expenditure was measured by indirect calorimetry. Anti-MLKL effects were also evaluated in in vitro setting using U937 and HepG2 cells. RESULTS: Hepatic tissue MLKL expression increased in NAFLD patients compared with healthy controls. MLKL expression increased according to the degree of steatosis, ballooning, and inflammation. High-fat diet-fed MLKL-KO mice displayed decreased alanine aminotransferase, triglycerides, liver weight, NAFLD activity score (6.3 vs 3.5, P < 0.001), steatosis score (3.0 vs 1.8, P < 0.001), inflammation, and ballooning degeneration compared with wild-type mice. SREBP1c, fatty acid synthase, and SCD-1 expressions decreased in MLKL-KO mice. Adipose tissue F4/80-positive crown-like structures were also reduced in MLKL-KO mice. HepG2 cells treated with necrosulfonamide (an MLKL inhibitor) showed reduced Nile red staining and reduced SREBP1c and SCD-1 expressions. Stimulation of necroptosis using lipopolysaccharide + caspase inhibitor (zVAD) increased CXCL1/2 expressions in U937 monocyte cells. Lipopolysaccharide + zVAD-induced increased expressions of CXCL1/2 were reduced with necrosulfonamide treatment. CONCLUSIONS: Mixed lineage kinase domain-like pseudokinase inhibition has protective effects in non-alcoholic steatohepatitis by decreasing hepatic de novo fat synthesis and chemokine (C-X-C motif) ligand expressions.
BACKGROUND AND AIM: Receptor-interacting serine/threonine kinase 3 and mixed lineage kinase domain-like pseudokinase (MLKL) have gained attention as apoptosis alternate cell death signaling molecules. We aimed to evaluate the role of MLKL in non-alcoholic fatty liver disease (NAFLD). METHODS: Hepatic tissue MLKL expression was compared between NAFLD patients and healthy controls. High-fat diet was fed to wild-type and MLKL-knockout (KO) mice for 12 weeks. Brown adipose fat tissue was measured by [18 F]-fluorodeoxyglucose positron emission tomography. Energy expenditure was measured by indirect calorimetry. Anti-MLKL effects were also evaluated in in vitro setting using U937 and HepG2 cells. RESULTS: Hepatic tissue MLKL expression increased in NAFLD patients compared with healthy controls. MLKL expression increased according to the degree of steatosis, ballooning, and inflammation. High-fat diet-fed MLKL-KO mice displayed decreased alanine aminotransferase, triglycerides, liver weight, NAFLD activity score (6.3 vs 3.5, P < 0.001), steatosis score (3.0 vs 1.8, P < 0.001), inflammation, and ballooning degeneration compared with wild-type mice. SREBP1c, fatty acid synthase, and SCD-1 expressions decreased in MLKL-KO mice. Adipose tissue F4/80-positive crown-like structures were also reduced in MLKL-KO mice. HepG2 cells treated with necrosulfonamide (an MLKL inhibitor) showed reduced Nile red staining and reduced SREBP1c and SCD-1 expressions. Stimulation of necroptosis using lipopolysaccharide + caspase inhibitor (zVAD) increased CXCL1/2 expressions in U937 monocyte cells. Lipopolysaccharide + zVAD-induced increased expressions of CXCL1/2 were reduced with necrosulfonamide treatment. CONCLUSIONS:Mixed lineage kinase domain-like pseudokinase inhibition has protective effects in non-alcoholic steatohepatitis by decreasing hepatic de novo fat synthesis and chemokine (C-X-C motif) ligand expressions.
Authors: Jan Korbecki; Iwona Szatkowska; Patrycja Kupnicka; Wojciech Żwierełło; Katarzyna Barczak; Iwona Poziomkowska-Gęsicka; Jerzy Wójcik; Dariusz Chlubek; Irena Baranowska-Bosiacka Journal: Int J Mol Sci Date: 2022-06-28 Impact factor: 6.208
Authors: Christian Liedtke; Yulia A Nevzorova; Tom Luedde; Henning Zimmermann; Daniela Kroy; Pavel Strnad; Marie-Luise Berres; Jürgen Bernhagen; Frank Tacke; Jacob Nattermann; Ulrich Spengler; Tilman Sauerbruch; Alexander Wree; Zeinab Abdullah; René H Tolba; Jonel Trebicka; Twan Lammers; Christian Trautwein; Ralf Weiskirchen Journal: Front Med (Lausanne) Date: 2022-01-11
Authors: Tamás Molnár; Anett Mázló; Vera Tslaf; Attila Gábor Szöllősi; Gabriella Emri; Gábor Koncz Journal: Cell Death Dis Date: 2019-11-12 Impact factor: 8.469