title: Protective role of endogenous plasmalogens against hepatic steatosis and steatohepatitis in mice.
abstract: Free cholesterol (FC) accumulation in the liver is an important pathogenic mechanism of nonalcoholic steatohepatitis (NASH). Plasmalogens, key structural components of the cell membrane, act as endogenous antioxidants and are primarily synthesized in the liver. However, the role of hepatic plasmalogens in metabolic liver disease is unclear. In this study, we found that hepatic levels of docosahexaenoic acid (DHA)-containing plasmalogens, expression of glyceronephosphate O-acyltransferase (Gnpat; the rate-limiting enzyme in plasmalogen biosynthesis), and expression of Pparα were lower in mice with NASH caused by accumulation of FC in the liver. Cyclodextrin-induced depletion of FC transactivated Δ-6 desaturase by increasing sterol regulatory element-binding protein 2 expression in cultured hepatocytes. DHA, the major product of Δ-6 desaturase activation, activated GNPAT, thereby explaining the association between high hepatic FC and decreased Gnpat expression. Gnpat small interfering RNA treatment significantly decreased peroxisome proliferator-activated receptor α (Pparα) expression in cultured hepatocytes. In addition to GNPAT, DHA activated PPARα and increased expression of Pparα and its target genes, suggesting that DHA in the DHA-containing plasmalogens contributed to activation of PPARα. Accordingly, administration of the plasmalogen precursor, alkyl glycerol (AG), prevented hepatic steatosis and NASH through a PPARα-dependent increase in fatty acid oxidation. Gnpat+/-mice were more susceptible to hepatic lipid accumulation and less responsive to the preventive effect of fluvastatin on NASH development, suggesting that endogenous plasmalogens prevent hepatic steatosis and NASH.
  
  
  
  Increased hepatic FC in animals with NASH decreased plasmalogens, thereby sensitizing animals to hepatocyte injury and NASH. Our findings uncover a novel link between hepatic FC and plasmalogen homeostasis through GNPAT regulation. Further study of AG or other agents that increase hepatic plasmalogen levels may identify novel therapeutic strategies against NASH. (Hepatology 2017;66:416-431).
authors.affiliation: Department of Internal Medicine, University of Ulsan College of Medicine, Seoul, Republic of Korea.|Asan Institute for Life Sciences, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Jung Eun
authors.initials: JE
authors.lastname: Jang
authors.affiliation: Asan Institute for Life Sciences, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Han-Sol
authors.initials: HS
authors.lastname: Park
authors.affiliation: Asan Institute for Life Sciences, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Hyun Ju
authors.initials: HJ
authors.lastname: Yoo
authors.affiliation: Asan Institute for Life Sciences, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: In-Jeoung
authors.initials: IJ
authors.lastname: Baek
authors.affiliation: Asan Institute for Life Sciences, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Ji Eun
authors.initials: JE
authors.lastname: Yoon
authors.affiliation: Asan Institute for Life Sciences, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Myoung Seok
authors.initials: MS
authors.lastname: Ko
authors.affiliation: Asan Institute for Life Sciences, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Ah-Ram
authors.initials: AR
authors.lastname: Kim
authors.affiliation: Asan Institute for Life Sciences, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Hyoun Sik
authors.initials: HS
authors.lastname: Kim
authors.affiliation: Asan Institute for Life Sciences, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Hye-Sun
authors.initials: HS
authors.lastname: Park
authors.affiliation: Department of Internal Medicine, University of Ulsan College of Medicine, Seoul, Republic of Korea.|Asan Institute for Life Sciences, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Seung Eun
authors.initials: SE
authors.lastname: Lee
authors.affiliation: Department of Pharmacology, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Seung-Whan
authors.initials: SW
authors.lastname: Kim
authors.affiliation: Asan Institute for Life Sciences, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Su Jung
authors.initials: SJ
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Jaechan
authors.initials: J
authors.lastname: Leem
authors.affiliation: Department of Internal Medicine, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Yu Mi
authors.initials: YM
authors.lastname: Kang
authors.affiliation: Asan Institute for Life Sciences, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Min Kyo
authors.initials: MK
authors.lastname: Jung
authors.affiliation: Asan Institute for Life Sciences, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Chan-Gi
authors.initials: CG
authors.lastname: Pack
authors.affiliation: Asan Institute for Life Sciences, University of Ulsan College of Medicine, Seoul, Republic of Korea.|Department of Pathology, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Chong Jai
authors.initials: CJ
authors.lastname: Kim
authors.affiliation: Department of Pathology, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Chang Ohk
authors.initials: CO
authors.lastname: Sung
authors.affiliation: Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu, Republic of Korea.
authors.forename: In-Kyu
authors.initials: IK
authors.lastname: Lee
authors.affiliation: Department of Internal Medicine, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Joong-Yeol
authors.initials: JY
authors.lastname: Park
authors.affiliation: Department of Cell Death and Proliferation, Biomedical Research Networking Center Consortium in Hepatic and Digestive diseases (CIBEREHD), Barcelona, Spain.|University of Southern California Research Center for Alcoholic Liver and Pancreatic Diseases and Cirrhosis, Keck School of Medicine, USC, Los Angeles, CA.
authors.forename: José C
authors.initials: JC
authors.lastname: Fernández-Checa
authors.affiliation: Department of Internal Medicine, University of Ulsan College of Medicine, Seoul, Republic of Korea.|Asan Institute for Life Sciences, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Eun Hee
authors.initials: EH
authors.lastname: Koh
authors.affiliation: Department of Internal Medicine, University of Ulsan College of Medicine, Seoul, Republic of Korea.|Asan Institute for Life Sciences, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Ki-Up
authors.initials: KU
authors.lastname: Lee
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001707:Biopsy, Needle; D004195:Disease Models, Animal; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology; D005234:Fatty Liver / Q000378:metabolism* / Q000473:pathology; D000077340:Fluvastatin; D051081:Glucosamine 6-Phosphate N-Acetyltransferase / Q000187:drug effects / Q000378:metabolism*; D007150:Immunohistochemistry; D007211:Indoles / Q000494:pharmacology; D008297:Male; D056913:Mediator Complex Subunit 1 / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D065626:Non-alcoholic Fatty Liver Disease / Q000378:metabolism / Q000473:pathology; D010955:Plasmalogens / Q000378:metabolism*; D011897:Random Allocation; D012680:Sensitivity and Specificity; D015398:Signal Transduction
chemical_list: D015415:Biomarkers; D005229:Fatty Acids, Monounsaturated; D007211:Indoles; D056913:Mediator Complex Subunit 1; D010955:Plasmalogens; D000077340:Fluvastatin; C494970:GNPNAT1 protein, human; D051081:Glucosamine 6-Phosphate N-Acetyltransferase