title: Effects of a farnesoid X receptor antagonist on hepatic lipid metabolism in primates.
abstract: We aimed to elucidate the mechanism underlying the anti-dyslipidemic effect of compound-T3, a farnesoid X receptor antagonist, by investigating its effects on hepatic lipid metabolism in non-human primates. We administered lipid-lowering drugs for 7 days to cynomolgus monkeys receiving a high-fat diet, and subsequently measured the levels of lipid parameters in plasma, feces, and hepatic tissue fluids. Compound-T3 (0.3 and 3mg/kg p.o.) significantly decreased the plasma levels of non-high-density lipoprotein (non-HDL) cholesterol and apolipoprotein B in a dose-dependent manner. It also decreased the mRNA levels of hepatic small heterodimer partner-1, induced the mRNA expression of hepatic cholesterol 7α-hydroxylase, reduced hepatic cholesterol and triglyceride levels, increased fecal bile acid excretion, and upregulated the expression of hepatic low-density lipoprotein (LDL) receptor. Furthermore, compound-T3 significantly increased plasma HDL cholesterol and apolipoprotein A-I levels. The mRNA expression levels of hepatic apolipoprotein A-I tended to increase after compound-T3 treatment. Compound-T3 also induced accumulation of hepatic bile acids and decreased the mRNA expression levels of the hepatic bile acid export pump. The effects of cholestyramine (300mg/kg p.o.) on the plasma and hepatic lipid parameters were similar to those of compound-T3, and it increased fecal bile acid levels without causing accumulation of hepatic bile acids. These findings suggest that LDL receptor-mediated hepatic LDL incorporation due to cholesterol catabolism catalyzed by cholesterol 7α-hydroxylase decreases plasma non-HDL cholesterol levels. Upregulation of hepatic apolipoprotein A-I mRNA expression may partially contribute to the increase in HDL cholesterol levels mediated by compound-T3.
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1 Muraokahigashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan. Electronic address: yuichiro.amano@takeda.com.
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Amano
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1 Muraokahigashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Mitsuyuki
authors.initials: M
authors.lastname: Shimada
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1 Muraokahigashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Shotaro
authors.initials: S
authors.lastname: Miura
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1 Muraokahigashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Ryutaro
authors.initials: R
authors.lastname: Adachi
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1 Muraokahigashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Tozawa
mesh_terms: D000818:Animals; D016632:Apolipoprotein A-I / Q000235:genetics; D001565:Benzoates / Q000494:pharmacology* / Q000627:therapeutic use; D001647:Bile Acids and Salts / Q000378:metabolism; D002790:Cholesterol 7-alpha-Hydroxylase / Q000235:genetics; D002792:Cholestyramine Resin / Q000494:pharmacology; D059305:Diet, High-Fat; D005243:Feces / Q000737:chemistry; D005260:Female; D006903:Hydroxymethylglutaryl CoA Reductases / Q000235:genetics; D006949:Hyperlipidemias / Q000188:drug therapy / Q000378:metabolism*; D007191:Indazoles / Q000494:pharmacology* / Q000627:therapeutic use; D050356:Lipid Metabolism / Q000187:drug effects*; D057847:Lipid Regulating Agents / Q000494:pharmacology* / Q000627:therapeutic use; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008252:Macaca fascicularis; D008297:Male; D012333:RNA, Messenger / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors* / Q000235:genetics; D011973:Receptors, LDL / Q000235:genetics; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D016632:Apolipoprotein A-I; D001565:Benzoates; D001647:Bile Acids and Salts; D002790:Cholesterol 7-alpha-Hydroxylase; D002792:Cholestyramine Resin; D006903:Hydroxymethylglutaryl CoA Reductases; D007191:Indazoles; D057847:Lipid Regulating Agents; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D011973:Receptors, LDL; D000099150:Receptor, Farnesoid X-Activated; C099713:nuclear receptor subfamily 0, group B, member 2
keywords: Cholestyramine; Farnesoid X receptor antagonist; Hepatic lipid content; Hepatic mRNA expression; High-density lipoprotein cholesterol; Low-density lipoprotein cholesterol