Theranostics 2017; 7(6):1749-1769. doi:10.7150/thno.18415

Research Paper

SAK-HV Triggered a Short-period Lipid-lowering Biotherapy Based on the Energy Model of Liver Proliferation via a Novel Pathway

Chao Zhang, Zhiguang Huang, Haoran Jing, Wenliang Fu, Min Yuan, Wenrong Xia, Ling Cai, Xiangdong Gan, Yao Chen, Minji Zou, Minhui Long, Jiaxi Wang, Min Wang*✉, Donggang Xu*✉

Laboratory of Genome Engineering, Beijing Institute of Basic Medical Sciences, Beijing, PR China.
*These authors share corresponding authorship.

Abstract

The accumulations of excess lipids within liver and serum are defined as non-alcoholic fatty liver disease (NAFLD) and hyperlipemia respectively. Both of them are components of metabolic syndrome that greatly threaten human health. Here, a recombinant fusion protein (SAK-HV) effectively treated NAFLD and hyperlipemia in high-fat-fed ApoE-/- mice, quails and rats within just 14 days. Its triglyceride and cholesterol-lowering effects were significantly better than that of atorvastatin during the observation period. We explored the lipid-lowering mechanism of SAK-HV by the hepatic transcriptome analysis and serials of experiments both in vivo and in vitro. Unexpectedly, SAK-HV triggered a moderate energy and material-consuming liver proliferation to dramatically decrease the lipids from both serum and liver. We provided the first evidence that PGC-1α mediated the hepatic synthesis of female hormones during liver proliferation, and proposed the complement system-induced PGC-1α-estrogen axis via the novel STAT3-C/EBPβ-PGC-1α pathway in liver as a new energy model for liver proliferation. In this model, PGC-1α ignited and fueled hepatocyte activation as an “igniter”; PGC-1α-induced estrogen augmented the energy supply of PGC-1α as an “ignition amplifier”, then triggered the hepatocyte state transition from activation to proliferation as a “starter”, causing triglyceride and cholesterol-lowering effects via PPARα-mediated fatty acid oxidation and LDLr-mediated cholesterol uptake, respectively. Collectively, the SAK-HV-triggered distinctive lipid-lowering strategy based on the new energy model of liver proliferation has potential as a novel short-period biotherapy against NAFLD and hyperlipemia.

Keywords: non-alcoholic fatty liver disease (NAFLD), hyperlipemia, liver proliferation, PGC-1α, estrogen, biotherapy.

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How to cite this article:
Zhang C, Huang Z, Jing H, Fu W, Yuan M, Xia W, Cai L, Gan X, Chen Y, Zou M, Long M, Wang J, Wang M, Xu D. SAK-HV Triggered a Short-period Lipid-lowering Biotherapy Based on the Energy Model of Liver Proliferation via a Novel Pathway. Theranostics 2017; 7(6):1749-1769. doi:10.7150/thno.18415. Available from http://www.thno.org/v07p1749.htm