Chemical chaperone 4-phenyl butyric acid (4-PBA) reduces hepatocellular lipid accumulation and lipotoxicity through induction of autophagy

Abstract

Defective autophagy has been linked to lipotoxicity in several cellular models. We aimed to investigate autophagy in lipid-stimulated hepatoma (Huh7) cells and tested whether 4-phenyl butyric acid (4-PBA), a chemical chaperone, has a beneficial role in hepatic fat accumulation and lipotoxicity. We report that long-term (24 h) exposure of hepatocytes to palmitate block autophagic flux that leads to lipid accumulation and cell death. Western blotting analysis showed increased accumulation of SQSTM1/p62, and decreased expression of Beclin1 and Atg7 in palmitate-treated cells. Autophagy inhibition by 3-methyladenine (3-MA) in palmitate-treated cells neither increased SQSTMI/p62 accumulation nor cell death, thus suggesting complete blockade of autophagy by palmitate. 4-PBA reduced lipid accumulation and cell death that were associated with restoration of autophagy. siRNA-mediated knockdown of Atg7 and presence of autophagy inhibitors, 3-MA and chloroquine, resulted in the decrease in lipid-lowering effect of 4-PBA, suggesting that 4-PBA mediates its lipid-lowering effect via autophagy. Apoptotic parameters, including altered Bcl2:Bax ratio and PARP1 cleavage induced by palmitate, were improved by 4-PBA. Our results indicate that palmitate impairs autophagy and increases lipid accumulation in Huh7 cells, whereas 4-PBA plays a protective role in lipid accumulation and lipotoxicity through activation of autophagy.

Phenylbutyrate facilitates homeostasis of non-resolving inflammatory macrophages

“…60,61 More recently, it has also been implicated in peroxisome biogenesis 62,63 and regulation of the cellular process autophagy. 35,36,55,64,65 These studies suggest a wide range of possible activities by 4-PBA that are highly dependent on the cell type, dosage, and treatment regime. However, as alluded to previously, very few of these studies have been conducted in the context of macrophage polarization by LPS.…”

4-PBA ameliorates cellular homeostasis in fibroblasts from osteogenesis imperfecta patients by enhancing autophagy and stimulating protein secretion

“…Treated mutant fibroblasts showed a significant increase of LC3II expression, highlighting a role for 4-PBA as autophagic inducer and suggesting a complementary process of autophagy may favor the degradation of retained unfolded proteins [ 55 ]. Indeed 4-PBA-mediated autophagy upregulation has been recently described in hepatocyte cells [ 56 ] and induction of autophagy rescued the bone matrix deposition by cultured osteoblasts of the OI Amish model [ 9 ]. Moreover, autophagy was reported to play an essential role in protecting cells against the toxicity of TGF-β induced type I procollagen accumulation in the ER [ 57 ].…”

Ammonia and autophagy: An emerging relationship with implications for disorders with hyperammonemia

“…Furthermore, activation of autophagy should be considered as a mechanism of action of drugs under investigation for hyperammonemia. Notably, sodium phenylbutyrate used as ammonia scavenger in urea cycle disorders has been also reported to activate autophagy in liver cells …”