Neddylation-mediated degradation of hnRNPA2B1 contributes to hypertriglyceridemia pancreatitis

Abstract

Hypertriglyceridemia-induced acute pancreatitis (HTGP) is characterized by the acute and excessive release of FFA produced by pancreatic lipases. However, the underlying mechanisms of this disease remain poorly understood. In this study, we describe the involvement of the RNA binding protein hnRNPA2B1 in the development of HTGP. We used palmitic acid (PA) and AR42J cells to create a model of HTGP in vitro. RT-PCR and western blot analyses revealed a decrease in the level of hnRNPA2B1 protein but not mRNA expression in PA-treated cells. Further analyses revealed that hnRNPA2B1 expression was regulated at the post-translational level by neddylation. Restoration of hnRNPA2B1 expression using the neddylation inhibitor MLN4924 protected AR42J cells from PA-induced inflammatory injury by preventing NF-κB activation and restoring fatty acid oxidation and cell proliferation. Furthermore, RNA immunoprecipitation studies demonstrated that hnRNPA2B1 orchestrates fatty acid oxidation by regulating the expression of the mitochondrial trifunctional protein-α (MTPα). Administration of MLN4924 in vivo restored hnRNPA2B1 protein expression in the pancreas of hyperlipidemic mice and ameliorated HTGP-associated inflammation and pancreatic tissue injury. In conclusion, we show that hnRNPA2B1 has a central regulatory role in preventing HTGP-induced effects on cell metabolism and viability. Furthermore, our findings indicate that pharmacological inhibitors that target neddylation may provide therapeutic benefits to HTGP patients.

Inositol polyphosphate multikinase modulates free fatty acids‐induced insulin resistance in primary mouse hepatocytes

“…39 It is also reported that PA treatment led to a reduction in heterogeneous nuclear ribonucleoproteins (hnRNPs) and serine-rich splicing factor 3 (SRSF3) protein levels by neddylationmediated proteasomal degradation in AR42J and HepG2 cells, respectively. 40,41 Since MG132 significantly prevented FFA-induced IPMK reduction, we speculate that FFAmediated modification of IPMK may trigger its degradation via proteasomal systems.…”

“…Saturated fatty acid such as PA has been shown to upregulate the proteolytic system in skeletal muscle, 36–38 and facilitates ubiquitination of cellular proteins leading to their degradation via the ubiquitin−proteasome pathway in HepG2 cells 39 . It is also reported that PA treatment led to a reduction in heterogeneous nuclear ribonucleoproteins (hnRNPs) and serine‐rich splicing factor 3 (SRSF3) protein levels by neddylation‐mediated proteasomal degradation in AR42J and HepG2 cells, respectively 40,41 . Since MG132 significantly prevented FFA‐induced IPMK reduction, we speculate that FFA‐mediated modification of IPMK may trigger its degradation via proteasomal systems.…”

IPMK modulates FFA-induced insulin resistance in primary mouse hepatocytes

“…Saturated fatty acid such as palmitic acid has been shown to upregulate the proteolytic system in skeletal muscle (Perry et al, 2018;Woodworth-Hobbs et al, 2014;Yang et al, 2013), and facilitates ubiquitination of cellular proteins leading to their degradation via the ubiquitinproteasome pathway in HepG2 cells (Ishii, Maeda, Tani, & Akagawa, 2015). It is also reported that PA treatment led to a reduction in heterogeneous nuclear ribonucleoproteins (hnRNPs) and serine-rich splicing factor 3 (SRSF3) protein levels by neddylation-mediated proteasomal degradation in AR42J and HepG2 cells, respectively (Chen, Wang, Xia, Zhang, & Zhao, 2022;Kumar et al, 2019). Since MG132 significantly prevented FFA-induced IPMK reduction, we speculate that FFA-mediated modification of IPMK may trigger its degradation via proteasomal systems.…”

Etitiological Relationship between Hyperlipidemia and Acute Pancreatitis

“…In conclusion, HnRNPA2B1 has an important regulatory role in preventing HTG damage to cells. Because neddylation is responsible for regulating the post-translational expression level of HnRNPA2B1, drugs targeting pharmacological inhibitors of neddylation may provide therapeutic benefit to patients with HTG-AP [66].…”