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.
Keywords: ER unfolded protein response; JNK signaling; flaxseed oil; hepatic steatosis; insulin resistance.