Autophagy protects against palmitate-induced apoptosis in hepatocytes

Abstract

BackgroundNon-alcoholic fatty liver disease, one of the most common liver diseases, has obtained increasing attention. Palmitate (PA)-induced liver injury is considered a risk factor for the development of non-alcoholic fatty liver disease. Autophagy, a cellular degradative pathway, is an important self-defense mechanism in response to various stresses. In this study, we investigated whether autophagy plays a protective role in the progression of PA-induced hepatocytes injury.ResultsAnnexin V-FITC/PI staining by FCM analysis, TUNEL assay and the detection of PARP and cleaved caspase3 expression levels demonstrated that PA treatment prominently induced the apoptosis of hepatocytes. Meanwhile, treatment of PA strongly induced the formation of GFP-LC3 dots, the conversion from LC3I to LC3II, the decrease of p62 protein levels and the increase of autophagosomes. These results indicated that PA also induced autophagy activation. Autophagy inhibition through chloroquine pretreatment or Atg5shRNA infection led to the increase of cell apoptosis after PA treatment. Moreover, induction of autophagy by pretreatment with rapamycin resulted in distinct decrease of PA-induced apoptosis. Therefore, autophagy can prevent hepatocytes from PA-induced apoptosis. In the further study, we explored pathway of autophagy activation in PA-treated hepatocytes. We found that PA activated PKCα in hepatocytes, and had no influence on mammalian target of rapamycin and endoplasmic reticulum stress pathways.ConclusionsThese results demonstrated that autophagy plays a protective role in PA-induced hepatocytes apoptosis. And PA might induce autophagy through activating PKCα pathway in hepatocytes.

LRP1 Protein Deficiency Exacerbates Palmitate-induced Steatosis and Toxicity in Hepatocytes

“…Thus, lipophagy impairment due to LRP1 deficiency may account for the increased sensitivity of hLrp1 Ϫ/Ϫ hepatocytes to palmitate-induced apo- ptosis. Previous studies have shown that lipophagy protects hepatocytes against oxidant stress and lipotoxicity (40,41). Thus, our observations that the elevated reactive oxygen species production and reduced viability of palmitate-treated hLrp1 Ϫ/Ϫ hepatocytes, which can be improved by the cysteine protease inhibitor E64D, provided additional support for the interpretation that LRP1 deficiency in hepatocytes impairs lipophagy to promote palmitate-induced lipid accumulation, lysosomal permeabilization, mitochondrial dysfunction, ER stress, and apoptosis.…”

Augmenter of liver regeneration protects against carbon tetrachloride-induced liver injury by promoting the autophagy in mice

“…Increasing reports shows that autophagy has a protective effect on liver injury [26][27][28]. Ni et al found that autophagy protected hepatocytes against acetaminophen (APAP)-induced necrosis, whereas the treatment of 3-MA or CQ further exacerbated necrosis [27].…”

Autophagy in the placenta

“…In fact, this protective effect was mediated by enhanced mitophagy, which reduced cytochrome c release and caspase activation [48]. Similar protective effects of enhanced autophagy were also demonstrated in palmitate-induced apoptosis in hepatocytes or oxidative stress-induced apoptosis in a rat model of Parkinson's disease [4950]. However, when excessive toxic signals threaten cells beyond this defense, ultimately apoptosis as well as autophagic cell death result.…”