ARS | Publication request: Familial combined hyperlipidemia is associated with alterations in the cholesterol synthesis pathway

Submitted to: Arteriosclerosis Thrombosis and Vascular Biology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: September 29, 2009
Publication Date: January 1, 2010
Citation: Van Himbergen, T.M., Otokozawa, S., Matthan, N.R., Schaefer, E.J., Buchsbaum, A., Ai, M., Van Tits, L.J., De Graaf, J., Stalenhoef, A.F. 2010. Familial combined hyperlipidemia is associated with alterations in the cholesterol synthesis pathway. Arteriosclerosis Thrombosis and Vascular Biology. 30:113-120.

Interpretive Summary: Familial combined hyperlipidemia (FCH) is one of the most common lipid disorders in the general population. FCH patients typically have elevated levels of cholesterol and triglycerides in their blood, and it is believed that there is a strong genetic component underlying these lipid elevations (hence the term 'familial' was used to name the disease). In this study, we wanted to know if the elevations in blood cholesterol levels were due to the synthesis of cholesterol by the body itself or the absorption of cholesterol from the diet, or a combination of the two. We found that patients with FCH, when compared to a group of people with a normal lipid profile, had higher levels of cholesterol synthesis markers in their blood, but the cholesterol absorption markers were relatively normal. This indicates that high cholesterol observed in FCH patients is more likely to be a problem of the cholesterol production than the absorption of cholesterol from the diet.

Technical Abstract: Familial combined hyperlipidemia (FCH) is a common familial lipid disorder characterized by increases in plasma total cholesterol, triglyceride, and apolipoprotein B-100 levels. In light of prior metabolic and genetic research, our purpose was to ascertain whether FCH cases had significant abnormalities of plasma markers of cholesterol synthesis and absorption as compared to unaffected kindred members. Plasma levels of squalene, desmosterol, and lathosterol (cholesterol synthesis markers) and campesterol, sitosterol, and cholestanol (cholesterol absorption markers) were measured by gas-liquid chromatography in 103 FCH patients and 240 normolipidemic relatives (NLR). Squalene, desmosterol, and lathosterol levels were 6% (0.078), 31%, (P_0.001) and 51% (P_0.001) higher in FCH as compared to NLR, and these differences were especially pronounced in women. An interaction with obesity was also noted for a subset of these markers. We did not observe any apparent differences for the cholesterol absorption markers among FCH patients and NLR. Our data indicates that both men and women with FCH have alterations in the cholesterol synthesis pathway, resulting in 51% higher levels of lathosterol (and additionally desmosterol in women). Plasma levels of the cholesterol precursor sterol squalene were only slightly increased (6%), suggesting enhanced conversion of squalene to lathosterol in this disorder.