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A study involving the IIS Aragón points to new early indicators of prediabetes related to cholesterol metabolism
A new study has identified an early mechanism associated with insulin resistance. The work, published in International Journal of Molecular Science proves that The absence of the enzyme CYP7B1, involved in cholesterol metabolism, causes an accumulation of 25-hydroxycholesterol, which alters the release of lipids from the liver..
These results are the product of a collaboration between several groups of the CIBER in the area of Obesity and Nutrition (CIBEROBN) and the area of Cardiovascular Diseases (CIBERCV) at the University of Zaragoza, the Institute of Nanoscience and Materials of Aragon (INMA), the Institute of Engineering Research of Aragon (I3A) and the University of Wisconsin.
“The deficiency of this CYP7B1 enzyme alters the hepatic metabolism of the system that exports lipids, as well as the levels of 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 along with Cristina Nerín, Martín Laclaustra, and Aron M. Geurts. The team adds that “it is considered that The hypersecretion of hepatic lipids in very low density lipoproteins (VLDL) is a phenomenon of resistance to the action of insulin, which was observed with normal glucose tolerance curves.These changes appear before glucose tolerance is altered, so they could be early indicators of prediabetes.
The teams studied male rats with the gene Cyp7b1 inactivated in the maternal and paternal copies and observed the absence of mRNA expression of Cyp7b1 in the liver, small intestine, adipose tissue, and muscle. Martín Lacaustra, a researcher at CIBERCV, the University of Zaragoza, and the Aragon Health Research Institute (IIS Aragón), explains that “Since this enzyme metabolizes cholesterol, we studied its metabolites and found elevated levels of 25-hydroxycholesterol in the livers of rats with the gene inactivated.Furthermore, he adds, “when these animals were subjected to fasting, their plasma triglyceride levels increased.”
Deactivate Cyp7b1 with CRISPR/Cas9 genetic engineering
To validate these results in a human model, lThe 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 gene expression in the two types of cells (modified and unmodified) and saw that the modified cells also showed changes in the FASN (Fatty Acid Synthase) enzyme, responsible for fatty acid synthesis, and IGFBP2, which reinforces the idea that the observed effects are not specific to the animal species,” the authors explain.
The head of the CIBEROBN group estimates that "having a marker like 25-hydroxycholesterol, which can be a very early indicator of the existence of prediabetes, can help to discriminate subjects at risk of progressing to diabetes and who require more controlled intervention from those for whom there is no such risk."
"So, CYP7B1 would be acting as an early regulator of liver metabolism, influencing lipid secretion and IGFBP2 expression,” the authors conclude.
The future direction 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.
Source: Ciber
