gamma-sitosterol and Lipid-Metabolism-Disorders

To examine recent advances in our knowledge on the diagnosis of lipid disorders.. Fasting values above the 99th percentile for direct LDL-cholesterol (LDL-C), lipoprotein(a), and triglycerides are greater than 225 mg/dl, greater than 160 mg/dl, and greater than 500 mg/dl (>5.82, >394, and >5.65 mmol/l), respectively, whereas such values for plasma lathosterol, β-sitosterol, and cholestanol are greater than 8.0, 8.0, and 5.0 mg/l (>0.021, 0.019, and 0.013 mmol/l), respectively. Values below the first percentile for LDL-C are less than 40 mg/dl (<1.03 mmol/l) and for HDL-cholesterol (HDL-C) less than 25 mg/dl (<0.65 mmol/l) in men and less than 30 mg/dl (<0.78 mmol/l) in women, respectively. The above values can predispose to premature CVD, pancreatitis, neurologic disease, and kidney failure, and may be associated with monogenic lipid disorders. In the absence of secondary causes including diabetes or kidney, liver, or thyroid disease, consideration should be given to sequencing the following genes: ABCA1, ABCG5, ABCG8, APOA1, APOA5, APOB, APOC2, APOE, CETP, CYP27A1, GPIHBP1, LCAT, LDLR, LDLRAP1, LIPA, LIPC, LMF1, LPL, MTTP, PCSK9, SCARB1, and STAP1.. Recent data indicate that secondary causes and a wider range of conditions need to be considered in identifying the underlying causes of hypercholesterolemia, hypertriglyceridemia, hyperalphalipoproteinemia, hypobetalipoproteinemia, and HDL deficiency. Identifying such disorders allows for a more precise assessment of prognosis and the formulation of optimal therapy.

Topics: Apolipoproteins; Biomarkers; Cardiovascular Diseases; Cholestanol; Cholesterol; Cholesterol, LDL; Fasting; Gene Expression; Genetic Predisposition to Disease; High-Throughput Nucleotide Sequencing; Humans; Lipid Metabolism Disorders; Lipoprotein(a); Mutation; Pancreatitis; Receptors, Lipoprotein; Sitosterols; Triglycerides

Cholesterol is esterified in mammals by two enzymes: LCAT (lecithin cholesterol acyltransferase) in plasma and ACAT(1) and ACAT(2) (acyl-CoA cholesterol acyltransferases) in the tissues. We hypothesized that the sterol structure may have significant effects on the outcome of esterification by these enzymes. To test this hypothesis, we analyzed sterol esters in plasma and tissues in patients having non-cholesterol sterols (sitosterolemia and Smith-Lemli-Opitz syndrome). The esterification of a given sterol was defined as the sterol ester percentage of total sterols. The esterification of cholesterol in plasma by LCAT was 67% and in tissues by ACAT was 64%. Esterification of nine sterols (cholesterol, cholestanol, campesterol, stigmasterol, sitosterol, campestanol, sitostanol, 7-dehydrocholesterol and 8-dehydrocholesterol) was examined. The relative esterification (cholesterol being 1.0) of these sterols by the plasma LCAT was 1.00, 0.95, 0.89, 0.40, 0.85, 0.82 and 0.80, 0.69 and 0.82, respectively. The esterification by the tissue ACAT was 1.00, 1.29, 0.75, 0.49, 0.45, 1.21 and 0.74, respectively. The predominant fatty acid of the sterol esters was linoleic acid for LCAT and oleic acid for ACAT. We compared the esterification of two sterols differing by only one functional group (a chemical group attached to sterol nucleus) and were able to quantify the effects of individual functional groups on sterol esterification. The saturation of the A ring of cholesterol increased ester formation by ACAT by 29% and decreased the esterification by LCAT by 5.9%. Esterification by ACAT and LCAT was reduced, respectively, by 25 and 11% by the presence of an additional methyl group on the side chain of cholesterol at the C-24 position. This data supports our hypothesis that the structure of the sterol substrate has a significant effect on its esterification by ACAT or LCAT.

Topics: Adolescent; Adult; Child; Child, Preschool; Esterification; Female; Humans; Infant; Infant, Newborn; Lipid Metabolism Disorders; Male; Phosphatidylcholine-Sterol O-Acyltransferase; Sitosterols; Smith-Lemli-Opitz Syndrome; Sterol O-Acyltransferase; Sterol O-Acyltransferase 2; Sterols; Young Adult