Abstract
Nonalcoholic fatty liver disease (NAFLD) is becoming more common in the world and is presenting a great challenge concerning prevention and treatment. Plant sterol ester of α-linolenic acid (PS-ALA) has a potential benefit to NAFLD. To examine the effect of PS-ALA on NAFLD, C57BL/6J mice were given a control diet, high fat and high cholesterol diet (HFD), and HFD plus 2% PS, 1.3% ALA, or 3.3% PS-ALA for 16 weeks. Our results showed that PS-ALA treatment suppressed hepatic steatosis, ameliorated lipid disorder, attenuated inflammatory response, and inhibited oxidative stress. In the molecular level, PS-ALA downregulated high transcriptional and translational levels of endoplasmic reticulum (ER) stress markers (Grp78 and Chop) leading to decreased protein expression of transcription factor and key enzymes involved in de novo lipogenesis (Srebp-1c and Fas) and cholesterol synthesis (Srebp-2 and Hmgcr). In parallel, PS-ALA blocked Nlrp3 activation and reduced release of IL-1β and IL-18 via inhibiting ER stress-induced sensitization of unfolded protein response sensors (Ire1α and Xbp1s). Finally, PS-ALA improved HFD-induced mitochondrial damage and fatty acid accumulation as exhibited by higher protein and mRNA expression of key genes administering mitochondrial biogenesis (Pgc-1α, Nrf1, and Tfam) and fatty acid β-oxidation (Pparα and Cpt1a). In conclusion, our study originally demonstrated that PS-ALA rescued ER stress, enhanced mitochondrial biogenesis, and thus ameliorated NAFLD.
Highlights
Nonalcoholic fatty liver disease (NAFLD) is becoming the most prevalent chronic liver disease around the world and the main cause of hepatocellular carcinoma (HCC), liver transplantation, and liver-related mortality [1]
endoplasmic reticulum (ER) stress may active a cascade of compensatory responses, called unfolded protein response (UPR), helping restore ER homeostasis and cell survival, persistent ER stress is known to enforce a detrimental pathological outcome, involving ectopic fat deposition, inflammation, oxidative stress, apoptosis, and dysregulated
This study demonstrated that Plant sterol (PS)-ALA was capable of ameliorating hepatic steatosis as well as optimizing lipid profiles, weakening inflammation, mitigating liver damage, and inhibiting oxidative stress induced by chronic lard-based HFD, which implied that PS attaching ALA had a good effect on protecting against nonalcoholic fatty liver disease (NAFLD)
Summary
Nonalcoholic fatty liver disease (NAFLD) is becoming the most prevalent chronic liver disease around the world and the main cause of hepatocellular carcinoma (HCC), liver transplantation, and liver-related mortality [1]. Evidence revealed that endoplasmic reticulum (ER) stress played a crucial role in the development of NAFLD [5]. ER is the main cell organ taking charge of protein folding, lipid biogenesis, and calcium homeostasis. Stressors that impair the folding capacity of the ER may lead to immature defective protein overflows and trigger ER stress [6]. ER stress may active a cascade of compensatory responses, called unfolded protein response (UPR), helping restore ER homeostasis and cell survival, persistent ER stress is known to enforce a detrimental pathological outcome, involving ectopic fat deposition, inflammation, oxidative stress, apoptosis, and dysregulated
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