Congratulations to Mengwei Zang, MD, PhD and the Zang Lab on their publication in Hepatology!
Dr. Zang is a Professor with the Sam and Ann Barshop Institute for Longevity and Aging Studies and the Department of Molecular Medicine. She is the Ewing Halsell Distinguished Chair in Research and the Associate Director of the MD/PhD Program at UT Health San Antonio. Importantly, this paper has established a fruitful collaboration with esteemed researchers: Dr. Bin Gao from NIH/NIAAA, Dr. Andrew C Adams from Eli Lilly and Company, and Dr. Jingyan Han from Boston University School of Medicine.
Targeting hepatic serine-arginine protein kinase 2 ameliorates alcohol-associated liver disease by alternative splicing control of lipogenesis
Guannan Li, Hanqing Chen, Feng Shen, Steven Blake Smithson, Gavyn Lee Shealy, Qinggong Ping, Zerong Liang, Jingyan Han, Andrew C Adams, Yu Li, Dechun Feng, Bin Gao, Masahiro Morita, Xianlin Han, Tim H Huang, Nicolas Musi, Mengwei Zang
Hepatology. 2023 May 3. doi: 10.1097/HEP.0000000000000433. Online ahead of print.
Background aims: Lipid accumulation induced by alcohol consumption is not only an early pathophysiological response but also a prerequisite for the progression of alcohol-associated liver disease (ALD). Alternative splicing regulates gene expression and protein diversity; dysregulation of this process is implicated in human liver diseases. However, how the alternative splicing regulation of lipid metabolism contributes to the pathogenesis of ALD remains undefined.
Approach results: Serine-arginine-rich protein kinase 2 (SRPK2), a key kinase controlling alternative splicing, is activated in hepatocytes in response to alcohol, in mice with chronic-plus-binge alcohol feeding, and in patients with ALD. Such induction activates sterol regulatory element binding transcription factor 1 (SREBP-1) and promotes lipogenesis in ALD. Overexpression of fibroblast growth factor 21 (FGF21) in transgenic mice abolishes alcohol-mediated induction of SRPK2 and its associated steatosis, lipotoxicity, and inflammation; these alcohol-induced pathologies are exacerbated in FGF21 knockout mice. Mechanistically, SRPK2 is required for alcohol-mediated impairment of serine-arginine splicing factor 10 (SRSF10), which generates exon 7 inclusion in lipin 1, and triggers concurrent induction of lipogenic regulators-lipin 1β and SREBP-1. FGF21 suppresses alcohol-induced SRPK2 accumulation through mTORC1 inhibition-dependent degradation of SRPK2. Silencing SRPK2 rescues alcohol-induced splicing dysregulation and liver injury in FGF21 knockout mice.
Conclusions: These studies reveal that 1) The regulation of alternative splicing by SRPK2 is implicated in lipogenesis in humans with ALD; 2) FGF21 is a key hepatokine that ameliorates ALD pathologies largely by inhibiting SRPK2; and 3) Targeting SRPK2 signaling by FGF21 may offer potential therapeutic approaches to combat ALD.
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