Up-regulation of hepatic fatty acid transporters and inhibition/down-regulation of hepatic OCTN2 contribute to olanzapine-induced liver steatosis

Jiang, Ting; Zhang, Yingqiong; Bai, Mengru; Li, Ping; Wang, Wei; Chen, Mingyang; Ma, Zhiyuan; Zeng, Su; Zhou, Hui; Jiang, Huidi

doi:10.1016/j.toxlet.2019.08.013

Cited by 23 publications

(13 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The mechanism of olanzapine-induced liver dysfunction remains unclear. A study by TingJiang showed that up-regulation of FATP2/FABP1 and down-regulation of hepatic OCTN2 probably contribute to olanzapine-induced liver steatosis ( Jiang et al, 2019 ).…”

Section: Discussionmentioning

confidence: 99%

Safety Profile of Antipsychotic Drugs: Analysis Based on a Provincial Spontaneous Reporting Systems Database

et al. 2022

View full text Add to dashboard Cite

Introduction: Antipsychotic drugs are the main therapy for schizophrenia and have been widely used in mental disorder fields. However, the research on the safety of antipsychotic drugs in the real-world is rare. The purpose of this research is to evaluate the safety of antipsychotic drugs based on real-world data.Methods: ADR reports collected by the Henan Adverse Drug Reaction Monitoring Center from 2016 to 2020 were analyzed. We described the safety of antipsychotic drugs by descriptive analysis and four signal mining methods. Meanwhile, the risk factors for serious adverse reactions of antipsychotics were identified.Results: A total of 3363 ADR reports related to antipsychotics were included. We found that the number of adverse drug reaction reports and the proportion of serious adverse reactions have increased year by year from 2016 to 2020. Most adverse drug reactions occurred within 3 months after taking the medicine. The symptoms caused by typical antipsychotics and atypical antipsychotics were different and dyskinesia was more common in typical antipsychotics. Most patients improved or recovered after treatment or intervention while only one patient had sequelae. Low-level hospitals, psychiatric hospitals, youth, and old age could increase the risk of serious adverse reactions. Four off-label signals were found through signal mining, including amisulpride-pollakiuria, ziprasidone-dyspnoea, quetiapine-urinary incontinence, olanzapine-hepatic function abnormal.Conclusion: We found that most ADRs occurred within 3 months after taking the medicine, so close observation was required for patients during the first 3 months of treatment. The ADRs of antipsychotics involved multiple organ-system damages but were not serious. It might be recommended to take alternative drugs after a serious ADR occurred. The symptoms caused by typical APDs and atypical APDs were different. For patients with typical APDs, dyskinesia was more common and should be given special attention. Statistics showed that low-level hospitals, psychiatric hospitals, youth, and old age were risk factors for serious ADRs. The four off-label signals obtained by signal mining should be paid special attention, including amisulpride-pollakiuria, ziprasidone-dyspnoea, quetiapine-urinary incontinence, and olanzapine-hepatic function abnormal.

show abstract

Section: Discussionmentioning

confidence: 99%

Safety Profile of Antipsychotic Drugs: Analysis Based on a Provincial Spontaneous Reporting Systems Database

et al. 2022

View full text Add to dashboard Cite

show abstract

“…Carnitine uptake experiments were performed in Madin–Darby canine kidney cells (MDCK) 87 , 88 . Briefly, MDCK cells stably overexpressing human OCTN2, MDCK-hOCTN2 cells, were plated in 24-well plates at a density of 2 × 10 5 /well.…”

Section: Methodsmentioning

confidence: 99%

Gut microbiota production of trimethyl-5-aminovaleric acid reduces fatty acid oxidation and accelerates cardiac hypertrophy

Zhao

Wei

et al. 2022

Nat Commun

Self Cite

View full text Add to dashboard Cite

Numerous studies found intestinal microbiota alterations which are thought to affect the development of various diseases through the production of gut-derived metabolites. However, the specific metabolites and their pathophysiological contribution to cardiac hypertrophy or heart failure progression still remain unclear. N,N,N-trimethyl-5-aminovaleric acid (TMAVA), derived from trimethyllysine through the gut microbiota, was elevated with gradually increased risk of cardiac mortality and transplantation in a prospective heart failure cohort (n = 1647). TMAVA treatment aggravated cardiac hypertrophy and dysfunction in high-fat diet-fed mice. Decreased fatty acid oxidation (FAO) is a hallmark of metabolic reprogramming in the diseased heart and contributes to impaired myocardial energetics and contractile dysfunction. Proteomics uncovered that TMAVA disturbed cardiac energy metabolism, leading to inhibition of FAO and myocardial lipid accumulation. TMAVA treatment altered mitochondrial ultrastructure, respiration and FAO and inhibited carnitine metabolism. Mice with γ-butyrobetaine hydroxylase (BBOX) deficiency displayed a similar cardiac hypertrophy phenotype, indicating that TMAVA functions through BBOX. Finally, exogenous carnitine supplementation reversed TMAVA induced cardiac hypertrophy. These data suggest that the gut microbiota-derived TMAVA is a key determinant for the development of cardiac hypertrophy through inhibition of carnitine synthesis and subsequent FAO.

show abstract

“…Emerging evidence suggests increased expression of FATP2 is linked to non-alcoholic fatty liver disease, renal disease and some cancers (2,(11)(12)(13). Under conditions of lipid overload, increased expression of FATP2 in the liver leads to increased fat accumulation, inflammation and organellar dysfunction (10,14,15). The selective inhibition of fatty acid (FA) transport using the FATP2-specific FA transport inhibitor, Lipofermata, attenuates palmitate-induced lipotoxicity in HepG2 cells and depresses fatty acid absorption across the intestine in mice (2,13,16).…”

mentioning

confidence: 99%

Deletion of fatty acid transport protein 2 (FATP2) in the mouse liver changes the metabolic landscape by increasing the expression of PPARα-regulated genes

Perez

Gabell

Behrens

et al. 2020

Journal of Biological Chemistry

View full text Add to dashboard Cite

Fatty acid transport protein 2 (FATP2) is highly expressed in the liver, small intestine, and kidney, where it functions in both the transport of exogenous long-chain fatty acids and the activation of very-long-chain fatty acids. Here, using a murine model, we investigated the phenotypic impacts of deleting FATP2, followed by a transcriptomic analysis using unbiased RNA-Seq to identify concomitant changes in the liver transcriptome. WT and FATP2-null (Fatp2−/−) mice (5 weeks) were maintained on a standard chow diet for 6 weeks. The Fatp2−/− mice had reduced weight gain, lowered serum triglyceride, and increased serum cholesterol levels and attenuated dietary fatty acid absorption. Transcriptomic analysis of the liver revealed 258 differentially expressed genes in male Fatp2−/− mice and a total of 91 in female Fatp2−/− mice. These genes mapped to the following gene ontology categories: fatty acid degradation, peroxisome biogenesis, fatty acid synthesis, and retinol and arachidonic acid metabolism. Targeted RT-quantitative PCR verified the altered expression of selected genes. Of note, most of the genes with increased expression were known to be regulated by peroxisome proliferator–activated receptor α (PPARα), suggesting that FATP2 activity is linked to a PPARα-specific proximal ligand. Targeted metabolomic experiments in the Fatp2−/− liver revealed increases of total C16:0, C16:1, and C18:1 fatty acids; increases in lipoxin A4 and prostaglandin J2; and a decrease in 20-hydroxyeicosatetraenoic acid. We conclude that the expression of FATP2 in the liver broadly affects the metabolic landscape through PPARα, indicating that FATP2 provides an important role in liver lipid metabolism through its transport or activation activities.

show abstract

Up-regulation of hepatic fatty acid transporters and inhibition/down-regulation of hepatic OCTN2 contribute to olanzapine-induced liver steatosis

Cited by 23 publications

References 40 publications

Safety Profile of Antipsychotic Drugs: Analysis Based on a Provincial Spontaneous Reporting Systems Database

Safety Profile of Antipsychotic Drugs: Analysis Based on a Provincial Spontaneous Reporting Systems Database

Gut microbiota production of trimethyl-5-aminovaleric acid reduces fatty acid oxidation and accelerates cardiac hypertrophy

Deletion of fatty acid transport protein 2 (FATP2) in the mouse liver changes the metabolic landscape by increasing the expression of PPARα-regulated genes

Contact Info

Product

Resources

About