H1-antihistamines exacerbate high-fat diet-induced hepatic steatosis in wild-type but not in apolipoprotein E knockout mice.
We examined the effects of two over-the-counter H1-antihistamines on the progression of fatty liver disease in male C57Bl/6 wild-type and apolipoprotein E (ApoE)-/- mice. Mice were fed a high-fat diet (HFD) for 3 mo, together with administration of either cetirizine (4 mg/kg body wt) or fexofenadine (40 mg/kg body wt) in drinking water. Antihistamine treatments increased body weight gain, gonadal fat deposition, liver weight, and hepatic steatosis in wild-type mice but not in ApoE-/- mice. Lobular inflammation, acute inflammation, and necrosis were not affected by H1-antihistamines in either genotype. Serum biomarkers of liver injury tended to increase in antihistamine-treated wild-type mice. Serum level of glucose was increased by fexofenadine, whereas lipase was increased by cetirizine. H1-antihistamines reduced the mRNA expression of ApoE and carbohydrate response element-binding protein in wild-type mice, without altering the mRNA expression of sterol regulatory element-binding protein 1c, fatty acid synthase, or ApoB100, in either genotype. Fexofenadine increased both triglycerides and cholesterol ester, whereas cetirizine increased only cholesterol ester in liver, with a concomitant decrease in serum triglycerides by both antihistamines in wild-type mice. Antihistamines increased hepatic levels of conjugated bile acids in wild-type mice, with the effect being significant in fexofenadine-treated animals. The increase was associated with changes in the expression of organic anion transport polypeptide 1b2 and bile salt export pump. These results suggest that H1-antihistamines increase the progression of fatty liver disease in wild-type mice, and there seems to be an association between the severity of disease, presence of ApoE, and increase in hepatic bile acid levels.
Division of Allergy, Clinical Immunology, and Rheumatology.
Vineesh V
VV
Raveendran
Department of Pharmacology, Toxicology, and Therapeutics.
Karen M
KM
Kassel
Division of Allergy, Clinical Immunology, and Rheumatology.
Donald D
DD
Smith
Department of Pharmacology, Toxicology, and Therapeutics, Pathobiology and Diagnostic Investigation, Michigan State University, East Lansing, Michigan.
James P
JP
Luyendyk
Pathobiology and Diagnostic Investigation, Michigan State University, East Lansing, Michigan.
Kurt J
KJ
Williams
Veterans Affairs Medical Center, Kansas City, Missouri;
Rachel
R
Cherian
Department of Pharmacology, Toxicology, and Therapeutics.
Gregory A
GA
Reed
Department of Pharmacology, Toxicology, and Therapeutics.
Colleen A
CA
Flynn
Division of Gastroenterology, Hepatology, and Motility, Department of Medicine, University of Kansas Medical Center, Kansas City, Kansas;
Iván L
IL
Csanaky
Division of Gastroenterology, Hepatology, and Motility, Department of Medicine, University of Kansas Medical Center, Kansas City, Kansas;
Andrew L
AL
Lickteig
Division of Gastroenterology, Hepatology, and Motility, Department of Medicine, University of Kansas Medical Center, Kansas City, Kansas;
Matthew J
MJ
Pratt-Hyatt
Division of Gastroenterology, Hepatology, and Motility, Department of Medicine, University of Kansas Medical Center, Kansas City, Kansas;
Curtis D
CD
Klaassen
Division of Allergy, Clinical Immunology, and Rheumatology, kdileepan@kumc.edu.
Kottarappat N
KN
Dileepan
D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D001647:Bile Acids and Salts / Q000378:metabolism; D015415:Biomarkers / Q000097:blood; D017332:Cetirizine / Q000633:toxicity*; D002788:Cholesterol Esters / Q000378:metabolism; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D005234:Fatty Liver / Q000097:blood / Q000139:chemically induced* / Q000235:genetics / Q000473:pathology; D005786:Gene Expression Regulation; D006634:Histamine H1 Antagonists / Q000633:toxicity*; D050155:Lipogenesis / Q000187:drug effects / Q000235:genetics; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D027381:Liver-Specific Organic Anion Transporter 1; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D029362:Organic Anion Transporters, Sodium-Independent / Q000235:genetics / Q000378:metabolism; D012720:Severity of Illness Index; D016593:Terfenadine / Q000031:analogs & derivatives* / Q000633:toxicity; D014280:Triglycerides / Q000378:metabolism
D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters; C490549:Abcb11 protein, mouse; D001057:Apolipoproteins E; D001647:Bile Acids and Salts; D015415:Biomarkers; D002788:Cholesterol Esters; D006634:Histamine H1 Antagonists; D027381:Liver-Specific Organic Anion Transporter 1; D029362:Organic Anion Transporters, Sodium-Independent; C498887:Slco1b2 protein, mouse; D014280:Triglycerides; D016593:Terfenadine; C093230:fexofenadine; D017332:Cetirizine
H1-antihistamines; bile acids; cetirizine; fexofenadine; steatosis