title: Lycopene and apo-10'-lycopenoic acid have differential mechanisms of protection against hepatic steatosis in β-carotene-9',10'-oxygenase knockout male mice.
abstract: BACKGROUND
  Nonalcoholic fatty liver disease is positively associated with obesity and cardiovascular disease risk. Apo-10'-lycopenoic acid (APO10LA), a potential oxidation product of apo-10'-lycopenal that is generated endogenously by β-carotene-9',10'-oxygenase (BCO2) cleavage of lycopene, inhibited hepatic steatosis in BCO2-expressing mice.
  
  
  OBJECTIVE
  The present study evaluated lycopene and APO10LA effects on hepatic steatosis in mice without BCO2 expression.
  
  
  METHODS
  Male and female BCO2-knockout (BCO2-KO) mice were fed a high saturated fat diet (HSFD) with or without APO10LA (10 mg/kg diet) or lycopene (100 mg/kg diet) for 12 wk.
  
  
  RESULTS
  Lycopene or APO10LA supplementation reduced hepatic steatosis incidence (78% and 72%, respectively) and severity in BCO2-KO male mice. Female mice did not develop steatosis, had greater hepatic total cholesterol (3.06 vs. 2.31 mg/g tissue) and cholesteryl ester (1.58 vs. 0.86 mg/g tissue), but had lower plasma triglyceride (TG) (229 vs. 282 mg/dL) and cholesterol (97.1 vs. 119 mg/dL) than male mice. APO10LA-mitigated steatosis in males was associated with reduced hepatic total cholesterol (18%) and activated sirtuin 1 signaling, which resulted in reduced fatty acids (FAs) and TG synthesis markers [stearoyl-coenzyme A (CoA) desaturase protein, 71%; acetyl-CoA carboxylase phosphorylation, 79%; AMP-activated protein kinase phosphorylation, 67%], and elevated cholesterol efflux genes (cytochrome P450 family 7A1, 65%; ATP-binding cassette transporter G5/8, 11%). These APO10LA-mediated effects were not mimicked by lycopene supplementation. Intriguingly, steatosis inhibition by lycopene induced peroxisome proliferator-activated receptor (PPAR)α- and PPARγ-related genes in mesenteric adipose tissue (MAT) that increases mitochondrial uncoupling [cell death-inducing DNA fragmentation factor, α subunit-like effector a, 55%; PR domain-containing 16, 47%; uncoupling protein 3 (Ucp3), 55%], FA β-oxidation (PPARα, 53%; very long chain acyl-CoA dehydrogenase, 38%), and uptake (FA transport protein 4, 29%; lipoprotein lipase 43%). Expressions of 10 MAT PPAR-related genes were inversely correlated with steatosis score, suggesting that lycopene reduced steatosis by increasing MAT FA utilization.
  
  
  CONCLUSIONS
  Our data suggest that lycopene and APO10LA inhibit HSFD-induced steatosis in BCO2-KO male mice through differential mechanisms. Sex disparity of BCO2-KO mice was observed in the outcomes of HSFD-induced liver steatosis and plasma lipids.
authors: Nutrition and Cancer Biology Laboratory, Friedman School of Nutrition Science and Policy, Tufts University, Boston, MA; and.
authors: Blanche C
authors: BC
authors: Ip
authors: Nutrition and Cancer Biology Laboratory.
authors: Chun
authors: C
authors: Liu
authors: Cardiovascular Nutrition Laboratory, Jean-Mayer USDA Human Nutrition Research Center on Aging, and Friedman School of Nutrition Science and Policy, Tufts University, Boston, MA; and.
authors: Alice H
authors: AH
authors: Lichtenstein
authors: Department of Pharmacology, School of Medicine, Case Western Reserve University, Cleveland, OH.
authors: Johannes
authors: J
authors: von Lintig
authors: Nutrition and Cancer Biology Laboratory, Friedman School of Nutrition Science and Policy, Tufts University, Boston, MA; and xiang-dong.wang@tufts.edu.
authors: Xiang-Dong
authors: XD
authors: Wang
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000103:Acetyl-CoA Carboxylase / Q000378:metabolism; D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D015415:Biomarkers / Q000097:blood; D002338:Carotenoids / Q000008:administration & dosage / Q000097:blood*; D002784:Cholesterol / Q000097:blood; D059305:Diet, High-Fat; D049308:Dioxygenases / Q000235:genetics* / Q000378:metabolism; D005227:Fatty Acids / Q000008:administration & dosage / Q000009:adverse effects; D005231:Fatty Acids, Unsaturated / Q000008:administration & dosage / Q000097:blood*; D005234:Fatty Liver / Q000188:drug therapy*; D005260:Female; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D000077276:Lycopene; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D047493:PPAR alpha / Q000235:genetics / Q000378:metabolism; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D015398:Signal Transduction; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism; D013230:Stearoyl-CoA Desaturase / Q000235:genetics / Q000378:metabolism; D014280:Triglycerides / Q000097:blood; D015854:Up-Regulation
chemical_list: D018528:ATP-Binding Cassette Transporters; D015415:Biomarkers; D005227:Fatty Acids; D005231:Fatty Acids, Unsaturated; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D047493:PPAR alpha; D047495:PPAR gamma; D014280:Triglycerides; C523199:apo-10'-lycopenoic acid; D002338:Carotenoids; D002784:Cholesterol; D049308:Dioxygenases; D013230:Stearoyl-CoA Desaturase; C481678:Bco2 protein, mouse; D055372:AMP-Activated Protein Kinases; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D000103:Acetyl-CoA Carboxylase; D000077276:Lycopene
keywords: PPAR; carotenoid metabolism; hepatic cholesterol; lipid metabolism; mesenteric adipose tissue; mitochondrial uncoupling; nonalcoholic fatty liver disease; obesity; plasma lipids; sirtuin 1
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