A Potential Link Between Dyslipidemia and Inflammation in Patients with Schizophrenia: Insights from Sterols and HDL Profile Analysis

Dyslipidemia and inflammation are two hallmarks of schizophrenia (SCZ), but the link between these two conditions remains elusive. We studied 40 SCZ patients and 40 age- and sex-matched healthy controls (CTRL) analyzing serum total, low-density lipoprotein (LDL), and high-density lipoprotein (HDL) cholesterol. In addition, we evaluated, for the first time in SCZ patients, HDL subfractions and surrogate markers of cholesterol intestinal absorption and de novo synthesis together with cholesterol precursors, aiming to address a possible dysregulation of cholesterol metabolism in SCZ. Moreover, we measured serum cytokines to evaluate systemic inflammation. SCZ patients showed an impaired cholesterol absorption, as indicated by serum phytosterols and cholestanol reduction, and a subsequent increase in de novo synthesis, confirmed by the increase in serum lathosterol. However, the last step of cholesterol biosynthesis seems to be impaired, probably for the inhibition of the 7-dehydrocholesterol reductase (DHCR7), as suggested by the significant increase in serum 7-dehydrocholesterol (and its isomer 8-dehydrocholesterol). Consequently, serum HDL cholesterol is significantly reduced with an anti-inflammatory remodeling of its subfractions that likely represents a response to systemic inflammation suggested by the increased serum interleukin-6 and angiopoietin-2 levels. Overall, the impaired cholesterol metabolism in SCZ patients is associated with a pro-inflammatory state, which is responded to by the anti-inflammatory remodeling of HDL subfractions. Improving intestinal cholesterol absorption and reducing endogenous cholesterol biosynthesis could represent putative therapeutic approaches.