Apoa4, also known as apolipoprotein A-IV, is a versatile apolipoprotein facilitating lipid transport and metabolism. It is synthesized in the small intestine, packaged onto chylomicrons, and secreted into intestinal lymph. Apoa4 may also be involved in anti-inflammatory responses [4]. It has been identified as a sphingosine 1-phosphate chaperone, supporting extracellular S1P signaling functions in the absence of ApoM and albumin [5]. A long non-coding RNA, APOA4-AS, has been shown to regulate ApoA4 expression depending on HuR in mice, and its knockdown leads to decreased levels of plasma triglyceride and total cholesterol in ob/ob mice [6].

Mutations in Apoa4 can cause autosomal dominant medullary amyloidosis, presenting as tubulointerstitial kidney disease with marked amyloid deposition limited to the kidney medulla [1]. Apoa4 may serve as a biomarker in several conditions. For example, serum APOA4 levels were found to be a pharmacodynamic marker of the recombinant human hepatocyte growth factor (E3112) [2], a novel predictor of prognosis in Stevens-Johnson syndrome/toxic epidermal necrolysis [3], and a circulating marker for predicting the progression of renal impairment in T2DM patients [7]. APOA4 polymorphism was associated with an unfavorable lipid serum profile and depression in a cross-sectional study [8].

In conclusion, Apoa4 plays essential roles in lipid transport, metabolism, and anti-inflammatory responses. Its mutations can lead to kidney-related amyloidosis. The study of Apoa4 through various genetic models, as seen in some of the research, has provided insights into its function in different disease conditions, such as in kidney diseases, drug response, and certain skin and metabolic disorders.

References:

1. Kmochová, Tereza, Kidd, Kendrah O, Orr, Andrew, Bleyer, Anthony J, Kmoch, Stanislav. 2023. Autosomal dominant ApoA4 mutations present as tubulointerstitial kidney disease with medullary amyloidosis. In Kidney international, 105, 799-811. doi:10.1016/j.kint.2023.11.021. https://pubmed.ncbi.nlm.nih.gov/38096951/

2. Motoi, Sotaro, Uesugi, Mai, Obara, Takashi, Imai, Toshio, Kawano, Tetsu. 2021. Serum APOA4 Pharmacodynamically Represents Administered Recombinant Human Hepatocyte Growth Factor (E3112). In International journal of molecular sciences, 22, . doi:10.3390/ijms22094578. https://pubmed.ncbi.nlm.nih.gov/33925510/

3. Gong, Ting, Zhang, Peng, Ruan, Shi-Fan, Chung, Wen-Hung, Ji, Chao. 2023. APOA4 as a novel predictor of prognosis in Stevens-Johnson syndrome/toxic epidermal necrolysis: A proteomics analysis from two prospective cohorts. In Journal of the American Academy of Dermatology, 89, 45-52. doi:10.1016/j.jaad.2023.02.058. https://pubmed.ncbi.nlm.nih.gov/36963506/

4. Zhang, Yupeng, He, Jing, Zhao, Jing, Li, Zongfang, Li, Xiaoming. 2017. Effect of ApoA4 on SERPINA3 mediated by nuclear receptors NR4A1 and NR1D1 in hepatocytes. In Biochemical and biophysical research communications, 487, 327-332. doi:10.1016/j.bbrc.2017.04.058. https://pubmed.ncbi.nlm.nih.gov/28412351/

5. Obinata, Hideru, Kuo, Andrew, Wada, Yukata, Izumi, Takashi, Hla, Timothy. 2019. Identification of ApoA4 as a sphingosine 1-phosphate chaperone in ApoM- and albumin-deficient mice. In Journal of lipid research, 60, 1912-1921. doi:10.1194/jlr.RA119000277. https://pubmed.ncbi.nlm.nih.gov/31462513/

6. Qin, Wangshu, Li, Xinzhi, Xie, Liwei, Zhou, Yifa, Chen, Zheng. 2016. A long non-coding RNA, APOA4-AS, regulates APOA4 expression depending on HuR in mice. In Nucleic acids research, 44, 6423-33. doi:10.1093/nar/gkw341. https://pubmed.ncbi.nlm.nih.gov/27131369/

7. Cheng, Chao-Wen, Chang, Che-Chang, Chen, Hsiu-Wen, Lin, Ching-Yu, Chen, Jin-Shuen. 2018. Serum ApoA4 levels predicted the progression of renal impairment in T2DM. In European journal of clinical investigation, 48, e12937. doi:10.1111/eci.12937. https://pubmed.ncbi.nlm.nih.gov/29675916/

8. Ota, Vanessa Kiyomi, Chen, Elizabeth Suchi, Ejchel, Tatiana Flank, Burbano, Rommel Rodriguez, Smith, Marília de Arruda Cardoso. . APOA4 polymorphism as a risk factor for unfavorable lipid serum profile and depression: a cross-sectional study. In Journal of investigative medicine : the official publication of the American Federation for Clinical Research, 59, 966-70. doi:10.2310/JIM.0b013e31822467cd. https://pubmed.ncbi.nlm.nih.gov/21712729/