H1-antihistamines exacerbate high-fat diet-induced hepatic steatosis in wild-type but not in apolipoprotein E knockout mice.

Abstract

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.

• Authors: Vineesh V Raveendran, Karen M Kassel, Donald D Smith, James P Luyendyk, Kurt J Williams, Rachel Cherian, Gregory A Reed, Colleen A Flynn, Iván L Csanaky, Andrew L Lickteig, Matthew J Pratt-Hyatt, Curtis D Klaassen, Kottarappat N Dileepan
• Journal: American journal of physiology. Gastrointestinal and liver physiology (Am J Physiol Gastrointest Liver Physiol) Vol. 307 Issue 2 Pg. G219-28 (Jul 15 2014) ISSN: 1522-1547 [Electronic] United States
• PMID: 24852568 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 the American Physiological Society.

Chemical References

• ATP Binding Cassette Transporter, Subfamily B, Member 11
• ATP-Binding Cassette Transporters
• Abcb11 protein, mouse
• Apolipoproteins E
• Bile Acids and Salts
• Biomarkers
• Cholesterol Esters
• Histamine H1 Antagonists
• Liver-Specific Organic Anion Transporter 1
• Organic Anion Transporters, Sodium-Independent
• Slco1b2 protein, mouse
• Triglycerides
• Terfenadine
• fexofenadine
• Cetirizine

Topics

• ATP Binding Cassette Transporter, Subfamily B, Member 11
• ATP-Binding Cassette Transporters (genetics, metabolism)
• Animals
• Apolipoproteins E (deficiency, genetics)
• Bile Acids and Salts (metabolism)
• Biomarkers (blood)
• Cetirizine (toxicity)
• Cholesterol Esters (metabolism)
• Diet, High-Fat
• Disease Models, Animal
• Fatty Liver (blood, chemically induced, genetics, pathology)
• Gene Expression Regulation
• Histamine H1 Antagonists (toxicity)
• Lipogenesis (drug effects, genetics)
• Liver (drug effects, metabolism, pathology)
• Liver-Specific Organic Anion Transporter 1
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Organic Anion Transporters, Sodium-Independent (genetics, metabolism)
• Severity of Illness Index
• Terfenadine (analogs & derivatives, toxicity)
• Triglycerides (metabolism)