A new study from the Center for Biomedical Research Network (CIBER), published in 'International Journal of Molecular Science', has identified that oxidized cholesterol metabolites could be early markers of prediabetes.
The work has shown that the absence of the CYP7B1 enzyme, involved in cholesterol metabolism, causes an accumulation of 25-hydroxycholesterol, which alters the output of lipids from the liver.
These results are the result of a collaboration between several CIBER groups from the Obesity and Nutrition area (CIBEROBN) and the Cardiovascular Diseases area (CIBERCV) at the University of Zaragoza, the Institute of Nanoscience and Materials of Aragon (INMA), the Engineering Research Institute of Aragon (I3A) and the University of Wisconsin (USA).
"The lack of this CYP7B1 enzyme alters the hepatic metabolism of the system that exports lipids, as well as the levels of the insulin-like growth factor binding protein 2 (IGFBP2)," explains Jesús de la Osada, group leader at CIBEROBN and one of the researchers leading the study together with Cristina Nerín, Martín Laclaustra and Aron M. Geurts.
The team adds that "the hypersecretion of hepatic lipids in very low density lipoproteins (VLDL) is considered to be a phenomenon of resistance to insulin action, which was observed with normal glucose tolerance curves."The changes appear before glucose tolerance changes, so they could be early indicators of prediabetes.
The teams studied male rats with the Cyp7b1 gene inactivated in the maternal and paternal copy and observed the absence of Cyp7b1 mRNA expression in the liver, small intestine, adipose tissue and muscle."Given that this enzyme metabolizes cholesterol, we studied its metabolites and found elevated levels of 25-hydroxycholesterol in the liver of rats with the gene inactivated," said Martín Lacaustra, researcher at CIBERCV, University of Zaragoza and Health Research Institute of Aragon.Furthermore, he added that "when these animals were fasted, plasma triglyceride levels increased."
To validate these results in a human model, the teams developed a liver cell line using CRISPR/cas9 techniques (a molecular tool used to edit or correct the genome of any cell) so that they did not have the CYP7B1 protein."We analyzed the gene expression in the two types of cells (modified and unmodified) and saw that the modified cells also showed changes in the enzyme FASN (Fatty Acid Synthase), the enzyme responsible for the synthesis of fatty acids, and IGFBP2, which reinforces the idea that the effects observed are not specific to the animal species," the authors explain.
The CIBEROBN group leader estimates that "having a marker such as 25-hydroxycholesterol, which can be a very early indicator of the existence of prediabetes, can help discriminate subjects at risk of progressing to diabetes and who require a more controlled intervention from those who do not have such a risk."
"Thus, CYP7B1 would be acting as an early regulator of hepatic metabolism, influencing lipid secretion and the expression of IGFBP2," the authors conclude.
The future line of this work will be to validate these metabolites in subjects who have metabolic syndrome, but do not have diabetes, as well as their changes with different diets.
