Plant Sterol Ester of α-Linolenic Acid Attenuates Nonalcoholic Fatty Liver Disease by Rescuing the Adaption to Endoplasmic Reticulum Stress and Enhancing Mitochondrial Biogenesis

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.

Pharmacology of bioactive compounds from plant extracts for improving non-alcoholic fatty liver disease through endoplasmic reticulum stress modulation: A comprehensive review

“…According to previous studies, the lipid compounds investigated in this study substantially decrease the expression of GRP78 and CHOP, which decelerate apoptosis and alleviate NAFLD [ [80] , [81] , [82] , [83] , [84] , [85] , [86] , [87] ]. These findings suggest that such compounds influence the upstream signalling pathways of ER stress, thereby unveiling a novel research avenue for exploring the molecular mechanisms by which lipid compounds regulate ER stress.…”

Effects of Omega-3-Rich Pork Lard on Serum Lipid Profile and Gut Microbiome in C57BL/6NJ Mice

“…However, the triglyceride levels of the omega lard-fed group were similar to those of the control group. The ALA in omega-3-rich pork lard, when used as a dietary ingredient, might reduce the levels of serum lipid at a higher magnitude compared with the ALA in coconut oil [ 20 , 21 ]. Similar results were reported in several preclinical trials.…”

The Role of Phytosterols in Nonalcoholic Fatty Liver Disease

“…In a study conducted by Hao Han et al on laboratory animals receiving a high fat and high cholesterol diet, administration of plant sterol ester of α-linolenic acid (PS-ALA) decreased liver size and body mass index, significantly improved liver tissue degradation, reduced oxidative stress, inhibited Sterol Regulatory Element-Binding Protein (Srebp) pathway activation, ameliorated lipid metabolism and thus intracellular fat accumulation, as well as inflammatory reaction (IL-1β, IL-18) and hepatocytolysis. The authors concluded that supplementation with PS-ALA leads to improvement of β-oxidation of fatty acids, by inhibiting ROS overproduction and enhanced mitochondrial biogenesis, which means it plays an important role in improvement of NAFLD [ 47 ].…”