Bile acid synthesis precursors in subjects with genetic hypercholesterolemia negative for LDLR/APOB/PCSK9/APOE mutations. Association with lipids and carotid atherosclerosis

Abstract

Some oxysterols are precursors of bile acid synthesis and play an important role in cholesterol homeostasis. However, if they are involved in the pathogeny of genetic hypercholesterolemia has not been previously explored. We have studied non-cholesterol sterol markers of cholesterol synthesis (lanosterol and desmosterol) and oxysterols (7α-hydroxy-4-cholesten-3-one, 24S-hydroxycholesterol and 27-hydroxycholesterol) in 200 affected subjects with primary hypercholesterolemia of genetic origin, negative for mutations in LDLR, APOB, PCSK9 and APOE genes (non-FH GH) and 100 normolipemic controls. All studied oxysterols and cholesterol synthesis markers were significantly higher in affected subjects than controls (P<0.001). Ratios of oxysterols to total cholesterol were higher in non-FH GH than in controls, although only 24S-hydroxycholesterol showed statistical significance (P<0.001). Cholesterol synthesis markers had a positive correlation with BMI, triglycerides, cholesterol and apoB in control population. However, these correlations disappeared in non-FH GH with the exception of a weak positive correlation for non-HDL cholesterol and apoB. The same pattern was observed for oxysterols with high positive correlation in controls and absence of correlation for non-FH GH, except non-HDL cholesterol for 24S-hydroxycholesterol and 27-hydroxycholesterol and apoB for 27-hydroxycholesterol. All non-cholesterol sterols had positive correlation among them in patients and in controls. A total of 65 (32.5%) and 35 (17.5%) affected subjects presented values of oxysterols ratios to total cholesterol above the 95th percentile of the normal distribution (24S-hydroxycholesterol and 27-hydroxycholesterol, respectively). Those patients with the highest levels of 24S-hydroxycholesterol associated an increase in the carotid intima media thickness. These results suggest that bile acid metabolism is affected in some patients with primary hypercholesterolemia of genetic origin, negative for mutations in the candidate genes, and may confer a higher cardiovascular risk. Our results confirm that cholesterol synthesis overproduction is a primary defect in non-HF GH and suggest that subjects with non-FH GH show high levels of oxysterols in response to hepatic overproduction of cholesterol.

Non-Cholesterol Sterol Concentrations as Biomarkers for Cholesterol Absorption and Synthesis in Different Metabolic Disorders: A Systematic Review

“…Three studies were performed in patients with Familial Combined Hyperlipidemia (FCH) [54,55,56], one study in patients with Familial Hypercholesterolemia (FH) [57], and four studies included patients with FCH, FH or another (non-FH) form of hypercholesterolemia [58,59,60,61]. Patients with hypercholesterolemia other than FCH of FH were evaluated in three studies [62,63,64].…”

“…In patients diagnosed with hypercholesterolemia other than FCH or FH, at least one of the cholesterol absorption markers increased in three comparisons [58,60,61], was comparable in two comparisons [64], and was not tested or measured in three comparisons [59,62,63]. One study reported higher cholesterol absorption in subjects diagnosed with heterogeneous autosomal dominant hypercholesterolemia compared to normolipidemic control subjects [61].…”

“…One study reported higher cholesterol absorption in subjects diagnosed with heterogeneous autosomal dominant hypercholesterolemia compared to normolipidemic control subjects [61]. For cholesterol synthesis, most comparisons did not find a difference between hypercholesterolemic cases and their controls [60,61,62,64], while cholesterol synthesis was suggested to be higher in one study [61] and lower in another study [58] in cases compared to controls. Two studies measured cholesterol synthesis, but did report differences between cases and control subjects, although it seems that cholesterol synthesis was lower in subjects with hypercholesterolemia [59,63].…”

Effects of dietary ascorbic acid levels on cholesterol metabolism in rainbow trout (Oncorhynchus mykiss)

“…Cholesterol homeostasis is achieved through the coordinated regulation of dietary cholesterol absorption, de novo biosynthesis, transportation (influx or efflux) and disposal in the form of bile acids (Baila‐Rueda et al, ; Shukla et al, ). The absorption of dietary cholesterol from the intestine is an important part of cholesterol homeostasis (Lu, Lee, & Patel, ).…”

Lipid Oxidation Derived Aldehydes and Oxysterols Between Health and Disease

“…The syntheses of 7α‐, 24‐ and 27‐hydroxycholesterol (7α‐HC, 24‐HC, 27‐HC) by action of their respective cholesterol hydroxylases, are the primary mechanisms preventing cholesterol accumulation . The hypothesis that oxysterols are synthesized in response to hepatic cholesterol over‐production has recently been strengthened by analyses conducted on 200 subjects with primary hypercholesterolemia of genetic origin: the bile acid precursors 7α‐hydroxy‐4‐cholesten‐3‐one, 24‐HC and 27‐HC were all significantly increased in the serum of patients versus controls …”