Liph-KO Mouse

LIPH, a member of the triglyceride lipase family, is a membrane-associated phosphatidic acid-selective phospholipase A1a. It can generate LPA from PA on the plasma membrane outer leaflet. The LIPH-LPA-LPAR6 signaling pathway is important, and LIPH dysfunction is linked to lipid metabolism disorders [1,8].

In pancreatic ductal adenocarcinoma (PDAC), LIPH is upregulated. Its down-regulation inhibits PDAC cell colony formation and proliferation. LIPH promotes tumor glycolysis by activating the LPA/LPAR axis, triggering the PI3K/AKT/HIF1A signaling pathway, and maintaining ALDOA stability in the cytosol. PDAC with high LIPH expression is sensitive to gemcitabine-based therapy [1].

In triple-negative breast cancer (TNBC), LIPH up-regulation promotes metastasis and stemness of TNBC cells. LIPH knockdown reduces the ratio and mammosphere-forming ability of CD44 + /CD24-stem-like cells, promotes apoptosis, arrests the cell cycle, and reduces metabolism [2].

In breast cancer, both mRNA and protein expression of LIPH are upregulated, and high LIPH expression is related to a lower overall survival rate [3].

In pancreatic cancer, LIPH overexpression is associated with tumor recurrence, advanced histologic grade, and poorer overall survival, and is correlated with immune suppression or evasion [5].

In esophageal squamous cell carcinoma (ESCC), a novel lncRNA LIPH-4 promotes ESCC progression through the miR-216b/IGF2BP2 axis [6].

Mutations in LIPH are responsible for autosomal recessive woolly hair/hypotrichosis in humans and the rex short-hair phenotype in rabbits [4,7,8].

In conclusion, LIPH is involved in multiple biological processes and disease conditions. Functional studies, especially those related to loss-of-function in relevant models (implied by the cell-based and patient-derived studies), have revealed its role in cancer progression, metastasis, metabolism, and hair-related disorders. Understanding LIPH can provide insights into disease mechanisms and potential therapeutic targets for cancers like PDAC, TNBC, breast cancer, pancreatic cancer, ESCC, as well as hair-related genetic diseases.

References:

1. Han, Lijie, Jiang, Yongsheng, Shi, Minmin, Jiang, Lingxi, Chen, Hao. 2023. LIPH contributes to glycolytic phenotype in pancreatic ductal adenocarcinoma by activating LPA/LPAR axis and maintaining ALDOA stability. In Journal of translational medicine, 21, 838. doi:10.1186/s12967-023-04702-6. https://pubmed.ncbi.nlm.nih.gov/37990271/

2. Zhang, Yixiao, Zhu, Xudong, Qiao, Xinbo, Cui, Meizi, Liu, Caigang. 2020. LIPH promotes metastasis by enriching stem-like cells in triple-negative breast cancer. In Journal of cellular and molecular medicine, 24, 9125-9134. doi:10.1111/jcmm.15549. https://pubmed.ncbi.nlm.nih.gov/32618099/

3. Gao, Peng, Liu, Qiang, Ai, Bolun, Wang, Zhongzhao, Wang, Jing. 2021. Prognostic Value and Clinical Significance of LIPH in Breast Cancer. In International journal of general medicine, 14, 7613-7623. doi:10.2147/IJGM.S332233. https://pubmed.ncbi.nlm.nih.gov/34754232/

4. Mizukami, Yukari, Hayashi, Ryota, Tsuruta, Daisuke, Shimomura, Yutaka, Sugawara, Koji. 2018. Novel splice site mutation in the LIPH gene in a patient with autosomal recessive woolly hair/hypotrichosis: Case report and published work review. In The Journal of dermatology, 45, 613-617. doi:10.1111/1346-8138.14257. https://pubmed.ncbi.nlm.nih.gov/29464811/

5. Zhuang, Hongkai, Chen, Xinming, Wang, Ying, Zhang, Chuanzhao, Hou, Baohua. 2021. Identification of LIPH as an unfavorable biomarkers correlated with immune suppression or evasion in pancreatic cancer based on RNA-seq. In Cancer immunology, immunotherapy : CII, 71, 601-612. doi:10.1007/s00262-021-03019-x. https://pubmed.ncbi.nlm.nih.gov/34279685/

6. Xiao, Yuhang, Tang, Jinming, Yang, Desong, Wang, Wenxiang, Su, Min. 2022. Long noncoding RNA LIPH-4 promotes esophageal squamous cell carcinoma progression by regulating the miR-216b/IGF2BP2 axis. In Biomarker research, 10, 60. doi:10.1186/s40364-022-00408-x. https://pubmed.ncbi.nlm.nih.gov/35971159/

7. Diribarne, Mathieu, Mata, Xavier, Rivière, Julie, Cribiu, Edmond-Paul, Guérin, Gérard. 2012. LIPH expression in skin and hair follicles of normal coat and Rex rabbits. In PloS one, 7, e30073. doi:10.1371/journal.pone.0030073. https://pubmed.ncbi.nlm.nih.gov/22272275/

8. Akiyama, M. 2021. Isolated autosomal recessive woolly hair/hypotrichosis: genetics, pathogenesis and therapies. In Journal of the European Academy of Dermatology and Venereology : JEADV, 35, 1788-1796. doi:10.1111/jdv.17350. https://pubmed.ncbi.nlm.nih.gov/33988877/