Adaptation of cholesterol synthesis to fasting and TNF-α: Profiling cholesterol intermediates in the liver, brain, and testis

Key players in pathogenesis of metabolic disorders are disturbed cholesterol balance and inflammation. In addition to cholesterol also sterol intermediates are biologically active, however, surprisingly little is known about their synthesis and roles. The aim of our study was to assess the interplay between the inflammatory cytokine TNF-α and cholesterol synthesis by measuring cholesterol and its intermediates in the liver, brain, and testis. Liquid chromatography-mass spectrometry has been applied to profile sterols of normally fed mice, during fasting and after TNF-α administration. In mice on normal chow diet, sterols other than cholesterol represent 0.5% in the liver, 1% in brain and 5% in testis. In the liver only 7-dehydrocholesterol, lanosterol and desmosterol were detected. Major sterol intermediates of the brain are desmosterol, testis meiosis activating sterol (T-MAS), and 7-dehydrocholesterol while in testis T-MAS predominates (4%), followed by desmosterol, lanosterol, 7-dehydrocholesterol and others. In 20. h fasting there is no significant change in cholesterol of the three tissues, and no significant change in intermediates of the liver. In the brain sterol intermediates are lowered (significant for zymosterol) while in the testis the trend is opposite. TNF-α provokes a significant raise of some intermediates whereas the level of cholesterol is again unchanged. The proportion of sterols in the liver rises from 0.5% in controls to 1.2% in TNF-α-treated mice, which is in accordance with published expression profiling data. In conclusion, our data provide novel insights into the interaction between the inflammatory cytokine TNF-α and the tissue-specific cholesterol biosynthesis of the liver, brain and testis.