Olanzapine, a representative of antipsychotics, is a first-line drug for treatment of schizophrenia. However, olanzapine-induced liver steatosis limits its clinical utilization. This study is to explore the mechanism of liver steatosis induced by olanzapine based on the regulation of transporters involved in uptake and oxidation of fatty acids. Our results revealed that 12-week oral administration of olanzapine increased hepatic triglyceride(TG), caused liver steatosis. Our further studies showed that the expression of fatty acid transporter 2(FATP2) and fatty acid binding protein 1(FABP1) were up-regulated in liver of female mice after 12-week olanzapine exposure, as well as in primary mouse hepatocytes treated with olanzapine. Olanzapine treatment also reduced hepatic β-hydroxybutyrate level (indicator of fatty acid β-oxidation), meanwhile, the L-carnitine (L-Car) concentration in liver of olanzapine group was significantly lower than that in control group. Further study demonstrated that both mRNA and protein expression of hepatic OCTN2 (carnitine/organic cation transporter 2) were obviously down-regulated in male mice after 12-week olanzapine treatment. Also, olanzapine markedly inhibited L-Car uptake in MDCK-hOCTN2 cells (1.06 μM of IC 50 ), HepG2 cells and primary mouse hepatocytes. Supplementation of L-Car attenuated hepatic TG rise and improved simple steatosis in olanzapine treatment mice. Taken together, up-regulation of FATP2/FABP1 and down-regulation/inhibition of hepatic OCTN2 probably contribute to olanzapine-induced liver steatosis. Supplementation of L-Car is a promising strategy to attenuate olanzapine-induced simple steatosis.
Longfei Lv,Sijie Zhang,Bing Huang,Li Ren,Jie Zhang,Zheng Ma
Cigarette consumption remains a preeminent global public health concern, as prolonged exposure to cigarette smoke is fundamentally implicated in the etiology of chronic pulmonary diseases and the manifestation of various malignancies. Apigenin, a bioactive dietary flavonoid widely distributes in botanical sources such as celery, demonstrates significant histoprotective effect. Nevertheless, the underlying mechanism governing apigenin's ability to counteract incipient pulmonary injury induced by cigarette smoke extract (CSE) remains to be delineated. By employing a novel CSE exposure system to establish reproducible in vivo and in vitro injury models, this study demonstrated that apigenin administration dose-dependently attenuates pulmonary apoptosis, as evidenced by the restoration of the Bax/Bcl-2 ratio and the suppression of Caspase-3 activation. Furthermore, apigenin treatment reversed the CSE-induced downregulation of PPARγ and its downstream effector, FATP2. Apigenin also restored intestinal mucosal integrity, promoted the enrichment of the probiotic Clostridia vadinBB60 group, and elevated intestinal difluprednate levels, which strongly correlated with increased glucocorticoid receptor (GR) expression in lung tissue. Mechanistically, apigenin facilitated the recruitment of PGC1α to PPARγ, thereby promoting PPARγ nuclear translocation and subsequent FATP2 activation in CSE-challenged MLE-12 cells. In RAW264.7 macrophages, difluprednate mediated GR nuclear translocation, subsequently suppressing the mRNA expression of the pro-inflammatory cytokines IL-1β and IL-6. Collectively, these findings identify apigenin as a dual-pathway modulator that bridges PPARγ/FATP2-mediated metabolic homeostasis with GR-dependent anti-inflammatory signaling, highlighting its therapeutic potential against smoking-related pulmonary dysfunction and supporting its application as a functional food intervention.
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