Dramatically increased intestinal absorption of cholesterol following hypophysectomy is normalized by thyroid hormone.
OBJECTIVE
Hypopituitarism is associated with dyslipidemia, and feeding hypophysectomized rats cholesterol induces severe hypercholesterolemia. This study aimed to unravel further how hypophysectomy alters cholesterol and bile acid metabolism.


METHODS
Intact and hypophysectomized rats were studied during challenge with dietary cholesterol and ezetimibe and upon hormonal substitution with growth hormone, cortisone, and thyroid hormone.


RESULTS
Five findings were established in hypophysectomized rats: (1) The intestinal absorption of cholesterol is doubled. (2) Treatment with ezetimibe abolishes the increases in serum and liver cholesterol. (3) Only thyroid hormone treatment normalizes the increased absorption of cholesterol. (4) The intestinal gene expression of cholesterol transporters NPC1L1 and ABCG5/G8 is unaltered, whereas the hepatic expression of ABCG5/G8 is diminished but strongly stimulated by thyroid hormone. The latter mechanism was supported by measurements of biliary cholesterol and of fecal neutral steroids. (5) The reduced hepatic expression of ABCG5/G8 and Cyp7a1 was normalized by cholesterol feeding, suggesting that other nonestablished mechanisms under pituitary control are important to maintain rats resistant to dietary cholesterol.


CONCLUSIONS
The intestinal absorption of dietary cholesterol is under pituitary control largely exerted by thyroid hormone. Hepatic secretion of cholesterol and ABCG5/G8 expression are strongly stimulated in hypophysectomized rats during treatment with thyroid hormone.
Gälman
Cecilia
C
Karolinska Institute, Center for Endocrinology, Metabolism, and Diabetes, Department of Medicine and Molecular Nutrition Unit, Center for Nutrition and Toxicology, Karolinska University Hospital, Huddinge, S-141 86 Stockholm, Sweden.
Bonde
Ylva
Y
Matasconi
Manuela
M
Angelin
Bo
B
Rudling
Mats
M
D000071018:ATP Binding Cassette Transporter, Subfamily G, Member 5; D000071019:ATP Binding Cassette Transporter, Subfamily G, Member 8; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage; D000924:Anticholesteremic Agents / Q000627:therapeutic use; D001384:Azetidines / Q000627:therapeutic use; D002784:Cholesterol / Q000378:metabolism*; D002791:Cholesterol, Dietary / Q000627:therapeutic use; D003348:Cortisone / Q000008:administration & dosage; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000235:genetics; D000072474:Cytochrome P450 Family 7; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D000069438:Ezetimibe; D005500:Follow-Up Studies; D008401:Gas Chromatography-Mass Spectrometry; D015870:Gene Expression; D006937:Hypercholesterolemia / Q000209:etiology / Q000378:metabolism / Q000628:therapy*; D007016:Hypophysectomy / Q000009:adverse effects*; D007018:Hypopituitarism / Q000150:complications / Q000378:metabolism* / Q000628:therapy; D007279:Injections, Subcutaneous; D007408:Intestinal Absorption / Q000187:drug effects*; D008074:Lipoproteins / Q000096:biosynthesis / Q000235:genetics; D008099:Liver / Q000378:metabolism; D008297:Male; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D013250:Steroid Hydroxylases / Q000096:biosynthesis / Q000235:genetics; D013974:Thyroxine / Q000008:administration & dosage*; D016896:Treatment Outcome
D000071018:ATP Binding Cassette Transporter, Subfamily G, Member 5; D000071019:ATP Binding Cassette Transporter, Subfamily G, Member 8; D018528:ATP-Binding Cassette Transporters; C480692:Abcg5 protein, rat; C480693:Abcg8 protein, rat; D000893:Anti-Inflammatory Agents; D000924:Anticholesteremic Agents; D001384:Azetidines; D002791:Cholesterol, Dietary; D008074:Lipoproteins; D012333:RNA, Messenger; D003577:Cytochrome P-450 Enzyme System; D002784:Cholesterol; D013250:Steroid Hydroxylases; D000072474:Cytochrome P450 Family 7; C490784:Cyp7b1 protein, rat; D000069438:Ezetimibe; D013974:Thyroxine; D003348:Cortisone