title: Treatment with Oxidized Phospholipids Directly Inhibits Nonalcoholic Steatohepatitis and Liver Fibrosis Without Affecting Steatosis.
abstract: Previous studies demonstrated that toll-like receptors 4 and 2 (TLR-4 and TLR-2), which are expressed on liver-resident Kupffer, hepatic stellate cells, and circulating monocytes, play a role in nonalcoholic fatty liver disease. Lecinoxoids are oxidized phospholipids that antagonize TLR-2- and TLR-4-mediated activation of innate immune cells and inhibit monocyte migration. In this study, we tested the effect of two functionally different lecinoxoids on the development of nonalcoholic steatohepatitis and liver fibrosis in a mouse model.
  
  
  
  Two-day-old C57BL/6 mice were injected with streptozotocin and fed a high-fat diet from Week 4 after birth. At Week 6 post-birth, lecinoxoids VB-201 or VB-703 were given orally, once daily, for 3 weeks. Telmisartan was administered orally, once daily, for 3 weeks, as positive control. At experiment conclusion, biochemical indices were evaluated. HE stain and quantitative PCR were used to determine the extent of steatosis and steatohepatitis, and Sirius red stain was used to assess liver fibrosis.
  
  
  
  Treatment with lecinoxoids did not alter the concentration of blood glucose, liver triglycerides, or steatosis compared with solvent-treated mice. However, whereas VB-201 inhibited the development of fibrosis and, to some extent, liver inflammation, VB-703 significantly lessened both liver inflammation and fibrosis.
  
  
  
  This study indicates that using lecinoxoids to antagonize TLR-2, and more prominently TLR-4, is sufficient to significantly inhibit nonalcoholic steatohepatitis and liver fibrosis. Inhibiting monocyte migration with lecinoxoids that are relatively weak TLR-4 antagonists may alter liver fibrosis and to some extent nonalcoholic steatohepatitis.
authors.affiliation: VBL Therapeutics, 6 Jonathan Netanyahu St., 6037604, Or Yehuda, Israel. Itzhak@vblrx.com.
authors.forename: Itzhak
authors.initials: I
authors.lastname: Mendel
authors.affiliation: VBL Therapeutics, 6 Jonathan Netanyahu St., 6037604, Or Yehuda, Israel.
authors.forename: Niva
authors.initials: N
authors.lastname: Yacov
authors.affiliation: VBL Therapeutics, 6 Jonathan Netanyahu St., 6037604, Or Yehuda, Israel.
authors.forename: Anat
authors.initials: A
authors.lastname: Shoham
authors.affiliation: VBL Therapeutics, 6 Jonathan Netanyahu St., 6037604, Or Yehuda, Israel.
authors.forename: Eti
authors.initials: E
authors.lastname: Ishai
authors.affiliation: VBL Therapeutics, 6 Jonathan Netanyahu St., 6037604, Or Yehuda, Israel.
authors.forename: Eyal
authors.initials: E
authors.lastname: Breitbart
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001562:Benzimidazoles / Q000494:pharmacology; D001565:Benzoates / Q000494:pharmacology; D001786:Blood Glucose; D015153:Blotting, Western; D002465:Cell Movement / Q000187:drug effects; D016207:Cytokines / Q000187:drug effects* / Q000378:metabolism; D003713:Dendritic Cells; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005994:Glycerophosphates / Q000494:pharmacology*; D005997:Glycerylphosphorylcholine / Q000494:pharmacology*; D055166:Hepatic Stellate Cells / Q000378:metabolism; D006801:Humans; D007249:Inflammation; D007728:Kupffer Cells / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000187:drug effects; D065626:Non-alcoholic Fatty Liver Disease / Q000378:metabolism*; D010743:Phospholipids / Q000494:pharmacology; D011726:Pyridinium Compounds / Q000494:pharmacology*; D060888:Real-Time Polymerase Chain Reaction; D000077333:Telmisartan; D051195:Toll-Like Receptor 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism
chemical_list: D000959:Antihypertensive Agents; D001562:Benzimidazoles; D001565:Benzoates; D001786:Blood Glucose; D016207:Cytokines; D005994:Glycerophosphates; D010743:Phospholipids; D011726:Pyridinium Compounds; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D014280:Triglycerides; C000621292:VB-703; D005997:Glycerylphosphorylcholine; C552500:1-palmityl-2-(4-carboxybutyl)-sn-glycero-3-phosphocholine; D000077333:Telmisartan
keywords: Fibrosis; Lecinoxoids; Nonalcoholic fatty liver disease; Nonalcoholic steatohepatitis; Toll-like receptor