Cholestasis and hypercholesterolemia in SCD1-deficient mice fed a low-fat, high-carbohydrate diet.
Stearoyl-coenzyme A desaturase 1-deficient (SCD1(-/-)) mice have impaired MUFA synthesis. When maintained on a very low-fat (VLF) diet, SCD1(-/-) mice developed severe hypercholesterolemia, characterized by an increase in apolipoprotein B (apoB)-containing lipoproteins and the appearance of lipoprotein X. The rate of LDL clearance was decreased in VLF SCD1(-/-) mice relative to VLF SCD1(+/+) mice, indicating that reduced apoB-containing lipoprotein clearance contributed to the hypercholesterolemia. Additionally, HDL-cholesterol was dramatically reduced in these mice. The presence of increased plasma bile acids, bilirubin, and aminotransferases in the VLF SCD1(-/-) mice is indicative of cholestasis. Supplementation of the VLF diet with MUFA- and PUFA-rich canola oil, but not saturated fat-rich hydrogenated coconut oil, prevented these plasma phenotypes. However, dietary oleate was not as effective as canola oil in reducing LDL-cholesterol, signifying a role for dietary PUFA deficiency in the development of this phenotype. These results indicate that the lack of SCD1 results in an increased requirement for dietary unsaturated fat to compensate for impaired MUFA synthesis and to prevent hypercholesterolemia and hepatic dysfunction. Therefore, endogenous MUFA synthesis is essential during dietary unsaturated fat insufficiency and influences the dietary requirement of PUFA.
Flowers
Matthew T
MT
Department of Biochemistry, University of Wisconsin-Madison, Madison, WI, USA.
Groen
Albert K
AK
Oler
Angie Tebon
AT
Keller
Mark P
MP
Choi
Younjeong
Y
Schueler
Kathryn L
KL
Richards
Oliver C
OC
Lan
Hong
H
Miyazaki
Makoto
M
Kuipers
Folkert
F
Kendziorski
Christina M
CM
Ntambi
James M
JM
Attie
Alan D
AD
D000818:Animals; D002779:Cholestasis / Q000097:blood / Q000209:etiology* / Q000378:metabolism / Q000517:prevention & control; D018752:Diet, Fat-Restricted / Q000009:adverse effects*; D004040:Dietary Carbohydrates / Q000008:administration & dosage*; D004042:Dietary Fats, Unsaturated / Q000008:administration & dosage; D005260:Female; D006937:Hypercholesterolemia / Q000097:blood / Q000209:etiology* / Q000378:metabolism / Q000517:prevention & control; D050356:Lipid Metabolism; D008055:Lipids / Q000097:blood; D008077:Lipoproteins, LDL / Q000097:blood / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008112:Liver Glycogen / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D013230:Stearoyl-CoA Desaturase / Q000172:deficiency* / Q000235:genetics; D014280:Triglycerides / Q000097:blood / Q000378:metabolism
D004040:Dietary Carbohydrates; D004042:Dietary Fats, Unsaturated; D008055:Lipids; D008077:Lipoproteins, LDL; D008112:Liver Glycogen; D014280:Triglycerides; C490333:Scd1 protein, mouse; D013230:Stearoyl-CoA Desaturase