HMG-CoA reductase, cholesterol 7alpha-hydroxylase, LDL receptor, SR-B1, and ACAT in diet-induced syndrome X.
BACKGROUND
Long-term consumption of Western diets can lead to acquired syndrome X, which presents with obesity, insulin resistance, hypertension, hyperlipidemia, and risk of atherosclerotic cardiovascular disease. While plasma lipid abnormalities in syndrome X have been well characterized, their molecular basis remains unclear. This study explored potential mechanisms of hypercholesterolemia in diet-induced syndrome X.


METHODS
Female Fischer rats were fed a high-fat, refined-carbohydrate (sucrose) diet (HFS) or standard rat chow (low-fat, complex carbohydrate, LFCC) for 20 months. Plasma lipids and hepatic tissue mRNA, protein, and/or activities of the key enzymes and receptors involved in cholesterol metabolism were determined.


RESULTS
The HFS group exhibited hypertension, hyperlipidemia, insulin resistance, obesity, significant down-regulation of hepatic cholesterol 7alpha-hydroxylase (the rate-limiting step in cholesterol catabolism) and low-density lipoprotein (LDL) receptor (LDL-R, the primary pathway of LDL clearance). In contrast, hepatic tissue acyl-coenzyme A:cholesterol acyltransferase (ACAT-2, the primary enzyme involved in intracellular esterification of cholesterol) and scavenger-receptor class B, type 1 (SR-B1 or HDL receptor) were up-regulated. While 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase mRNA expression was increased, its protein abundance and activity were unchanged, and HMG-CoA reductase-to-cholesterol 7alpha-hydroxylase ratio was increased in HFS-fed animals.


CONCLUSIONS
Hypercholesterolemia in diet-induced syndrome X is associated with depressed cholesterol 7alpha-hydroxylase, diminished LDL-R, elevated ACAT, and increased HMG-CoA reductase-to-cholesterol 7alpha-hydroxylase ratio. These findings point to impaired hepatic catabolism and uptake of cholesterol and inappropriate cholesterol production capacity as the underlying causes of hypercholesterolemia in rats with diet-induced syndrome X.
Roberts
Christian K
CK
Department of Physiological Science, University of California, Los Angeles, California, USA.
Liang
Kaihui
K
Barnard
R James
RJ
Kim
Choong H
CH
Vaziri
Nosratola D
ND
D000821:Animal Feed; D000818:Animals; D002790:Cholesterol 7-alpha-Hydroxylase / Q000378:metabolism*; D019422:Dietary Sucrose / Q000494:pharmacology; D005260:Female; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism*; D006949:Hyperlipidemias / Q000378:metabolism; D008099:Liver / Q000201:enzymology; D024821:Metabolic Syndrome / Q000378:metabolism*; D009765:Obesity / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D011971:Receptors, Immunologic / Q000378:metabolism*; D011973:Receptors, LDL / Q000378:metabolism*; D051116:Receptors, Scavenger; D051122:Scavenger Receptors, Class B; D002785:Sterol O-Acyltransferase / Q000378:metabolism*; D000097587:Sterol O-Acyltransferase 2
D002790:Cholesterol 7-alpha-Hydroxylase; D019422:Dietary Sucrose; D006903:Hydroxymethylglutaryl CoA Reductases; D011971:Receptors, Immunologic; D011973:Receptors, LDL; D051116:Receptors, Scavenger; D051122:Scavenger Receptors, Class B; D002785:Sterol O-Acyltransferase; D000097587:Sterol O-Acyltransferase 2; C495125:Scarb1 protein, rat