Lipidomics reveals carnitine palmitoyltransferase 1C protects cancer cells from lipotoxicity and senescence

Lipotoxicity, caused by intracellular lipid accumulation, accelerates the degenerative process of cellular senescence, which has implications in cancer development and therapy. Previously, carnitine palmitoyltransferase 1C(CPT1C), a mitochondrial enzyme that catalyzes carnitinylation of fatty acids, was found to be a critical regulator of cancer cell senescence. However, whether loss of CPT1C could induce senescence as a result of lipotoxicity remains unknown. An LC/MS-based lipidomic analysis of PANC-1,MDA-MB-231, HCT-116 and A549 cancer cells was conducted after siRNA depletion of CPT1C. Cellular lipotoxicity was further confirmed by lipotoxicity assays. Significant changes were found in the lipidome of CPT1C-depleted cells, including major alterations in fatty acid, diacylglycerol, triacylglycerol, oxidative lipids, cardiolipin, phosphatidylglycerol, phosphatidylcholine/phosphatidylethanolamine ratio and sphingomyelin. This was coincident with changes in expressions of mRNAs involved in lipogenesis.Histological and biochemical analyses revealed higher lipid accumulation and increased malondialdehyde and reactive oxygen species, signatures of lipid peroxidation and oxidative stress. Reduction of ATP synthesis, loss of mitochondrial transmembrane potential and down-regulation of expression of mitochondriogenesis gene m RNAs indicated mitochondrial dysfunction induced by lipotoxicity, which could further result in cellular senescence. Taken together, this study demonstrated CPT1C plays a critical role in the regulation of cancer cell lipotoxicity and cell senescence, suggesting that inhibition of CPT1C may serve as a new therapeutic strategy through induction of tumor lipotoxicity and senescence.

Dominant changes in the breast muscle lipid profiles of broiler chickens with wooden breast syndrome revealed by lipidomics analyses

Background: Chicken is the most consumed meat worldwide and the industry has been facing challenging myopathies. Wooden breast(WB), which is often accompanied by white striping(WS), is a serious myopathy adversely affecting meat quality of breast muscles. The underlying lipid metabolic mechanism of WB affected broilers is not fully understood.Results: A total of 150 chickens of a white-feathered, fast-growing pure line were raised and used for the selection of WB, WB + WS and control chickens. The lipids of the breast muscle, liver, and serum from different chickens were extracted and measured using ultra performance liquid chromatography(UPLC) plus Q-Exactive Orbitrap tandem mass spectrometry. In the breast, 560 lipid molecules were identified. Compared to controls, 225/225 of 560 lipid molecules(40.2%) were identified with differential abundance(DA), including 92/100 significantly increased neutral lipids and 107/98 decreased phospholipids in the WB/WB + WS groups, respectively. The content of monounsaturated fatty acids(MUFA) was significantly higher, and the polyunsaturated fatty acids(PUFA) and saturated fatty acids(SFA) were significantly lower in the affected breasts. In the liver, 434 lipid molecules were identified, and 39/61 DA lipid molecules(6.7%/14.1%) were detected in the WB and WB + WS groups, respectively. In the serum, a total of 529 lipid molecules were identified and 4/44 DA lipid molecules(0.8%/8.3%) were detected in WB and WB + WS group, respectively. Compared to controls, the content of MUFAs in the serum and breast of the WB + WS group were both significantly increased, and the content of SFAs in two tissues were both significantly decreased. Only five lipid molecules were consistently increased in both liver and serum in WB + WS group.Conclusions: We have found for the first time that the dominant lipid profile alterations occurred in the affected breast muscle. The relative abundance of 40.2% of lipid molecules were changed and is characteristic of increased neutral lipids and decreased phospholipids in the affected breasts. Minor changes of lipid profiles in the liver and serum of the affected groups were founded. Comprehensive analysis of body lipid metabolism indicated that the abnormal lipid profile of WB breast may be independent of the liver metabolism.

SIRT6 as a key event linking P53 and NRF2 counteracts APAP-induced hepatotoxicity through inhibiting oxidative stress and promoting hepatocyte proliferation

Acetaminophen(APAP)overdose is the leading cause of drug-induced liver injury,and its prognosis depends on the balance between hepatocyte death and regeneration.Sirtuin 6(SIRT6)has been reported to protect against oxidative stress-associated DNA damage.But whether SIRT6 regulates APAPinduced hepatotoxicity remains unclear.In this study,the protein expression of nuclear and total SIRT6 was up-regulated in mice liver at 6 and 48 h following APAP treatment,respectively.Sirt6 knockdown in AML12 cells aggravated APAP-induced hepatocyte death and oxidative stress,inhibited cell viability and proliferation,and downregulated CCNA1,CCND1 and CKD4 protein levels.Sirt6 knockdown signifi-cantly prevented APAP-induced NRF2 activation,reduced the transcriptional activities of GSTm andNQO1 and the m RNA levels of Nrf2,Ho-1,Gsta and Gstm.Furthermore,SIRT6 showed potential protein interaction with NRF2 as evidenced by co-immunoprecipitation(Co-IP)assay.Additionally,the protective effect of P53 against APAP-induced hepatocytes injury was Sirt6-dependent.The Sirt6 m RNA was significantly down-regulated in P53à/àmice.P53 activated the transcriptional activity of SIRT6 and exerted interaction with SIRT6.Our results demonstrate that SIRT6 protects against APAP hepatotoxicity through alleviating oxidative stress and promoting hepatocyte proliferation,and provide new insights in the function of SIRT6 as a crucial docking molecule linking P53 and NRF2.

Modeling Chinese Microblogs with Five Ws for Topic Hashtags Extraction

Hashtags are important metadata in microblogs and are used to mark topics or index messages. However,statistics show that hashtags are absent from most microblogs. This poses great challenges for the retrieval and analysis of these tagless microblogs. In this paper, we summarize the similarity between microblogs and shortmessage-style news, and then propose an algorithm, named 5WTAG, for detecting microblog topics based on a model of five Ws（When, Where, Who, What, ho W）. As five-W attributes are the core components in event description, it is guaranteed theoretically that 5WTAG can properly extract semantic topics from microblogs. We introduce the detailed procedure of the algorithm in this paper including spam microblog identification, microblog segmentation, and candidate hashtag construction. In addition, we propose a novel recommendation computing method for ranking candidate hashtags, which combines syntax and semantic analysis and observes the distribution of artificial topic hashtags. Finally, we conduct comprehensive experiments to verify the semantic correctness and completeness of the candidate hashtags, as well as the accuracy of the recommendation method using real data from Sina Weibo.