4.3 Article

Protein Phosphatase 4 Promotes Hepatocyte Lipoapoptosis by Regulating RAC1/MLK3/JNK Pathway

Journal

OXIDATIVE MEDICINE AND CELLULAR LONGEVITY
Volume 2021, Issue -, Pages -

Publisher

HINDAWI LTD
DOI: 10.1155/2021/5550498

Keywords

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Funding

  1. National Natural Science Foundation of China [81770858, 81600618, 81770228, 81270495, 81470427]
  2. National Key R&D Program of China [2018YFC2000100]
  3. Beijing Natural Science Foundation [7182144, 7212086]
  4. Beijing Hospital Nova Project [BJ-2018-138]
  5. Non-Profit Central Research Institute Fund of the Chinese Academy of Medical Sciences [2018RC310025]
  6. Qinghai Science and Technology Foundation [2019-ZJ-922]

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The study identified PP4 as a new regulator of hepatocyte lipoapoptosis. Inhibition of PP4 reduced SFA-induced JNK activation and expression of key modulators of lipoapoptosis, leading to decreased hepatocyte lipoapoptosis both in vitro and in vivo. PP4 was found to mediate hepatocyte lipoapoptosis by regulating the RAC1/MLK3/JNK signaling pathway.
Lipotoxicity-induced apoptosis, also referred to as lipoapoptosis, is one of the important initial factors promoting the progression from hepatosteatosis to nonalcoholic steatohepatitis (NASH). Saturated free fatty acids (SFAs), which are increased significantly in NASH, are directly hepatotoxic which induce hepatocyte lipoapoptosis. Previously, we reported that protein phosphatase 4 (PP4) was a novel regulator of hepatic insulin resistance and lipid metabolism, but its role in hepatic lipoapoptosis remains unexplored. In this study, we found out that PP4 was upregulated in the livers of western diet-fed-induced NASH mice and SFA-treated murine primary hepatocytes and HepG2 cells. In addition, we found for the first time that suppression of PP4 decreased SFA-induced JNK activation and expression of key modulators of hepatocyte lipoapoptosis including p53-upregulated modulator of apoptosis (PUMA) and Bcl-2-interacting mediator (Bim) and reduced hepatocyte lipoapoptosis level as well both in vitro and in vivo. Further study revealed that PP4 induced JNK activation and lipoapoptosis-related protein expression by regulating the RAC1/MLK3 pathway instead of the PERK/CHOP pathway. The effects of palmitate-treated and PP4-induced lipoapoptosis pathway activation were largely abolished by RAC1 inhibition. Moreover, we identified that PP4 interacted with RAC1 and regulated GTPase activity of RAC1. In conclusion, these results demonstrated that PP4 was a novel regulator of hepatocyte lipoapoptosis and mediated hepatocyte lipoapoptosis by regulating the RAC1/MLK3/JNK signaling pathway. Our finding provided new insights into the mechanisms of this process.

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