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Flaxseed Oil Attenuates Hepatic Steatosis and Insulin Resistance in Mice by Rescuing the Adaption to ER Stress

Yu, Xiao, Deng, Qianchun, Tang, Yuhan, Xiao, Lin, Liu, Liegang, Yao, Ping, Tang, Hu, Dong, Xuyan
Journal of agricultural and food chemistry 2018 v.66 no.41 pp. 10729-10740
animal models, biochemical pathways, dose response, endoplasmic reticulum, fatty liver, high fat diet, humans, inflammation, insulin receptors, insulin resistance, linseed oil, lipid composition, lipid metabolism disorders, liver, mice, mitogen-activated protein kinase, non-specific serine/threonine protein kinase, noninsulin-dependent diabetes mellitus, omega-3 fatty acids, phosphorylation, tyrosine, unfolded protein response
Increasing evidence has demonstrated the benefits of α-linolenic acid-rich flaxseed oil (ALA-FO) against lipid metabolism abnormality in both rodent models and humans. However, the metabolic response of FO to insulin resistance and type 2 diabetes is still inconsistent. This study aimed to explore the effect of FO on chronic high fat diet (HFD)-induced hepatic steatosis, insulin resistance, and inflammation, mainly focusing on hepatic n-3 fatty acid remodeling and endoplasmic reticulum (ER) unfolded protein response. The results showed that lard-based HFD feeding for 16 weeks (60% fat-derived calories) induced whole-body insulin resistance, lipid profile abnormality, and inflammation in mice, which was alleviated by FO in a dose-dependent manner. Moreover, FO effectively improved hepatic steatosis and insulin resistance in mice by modulating the specific location of ALA and its long-chain n-3 fatty acids across hepatic lipid fractions and enhancing insulin-stimulated phosphorylation of hepatic insulin receptor subtract-1 (IRS-1) tyrosine 632 and protein kinase B (AKT) (p < 0.05). Importantly, the differential depositions of ALA and its long-chain n-3 fatty acids in plasma and ER membranes were observed, concomitant with the rescued ER unfolded protein response and Jun N-terminal kinase (JNK) signaling in mice liver.