All mutations were introduced into the CYP3A5-57ins and CYP3A4-374 constructs using the QuikChange Site-Directed Mutagenesis Kit

can activate lipid-sensitive PKC isoforms such as -h and -e which phosphorylates the serine/threonine PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/22183719 residues of IRS to interrupt insulin-mediated phosphorylations at the tyrosine sites required for the signal transductions. Thus, while both HFat and HFru diets are capable of causing hepatic steatosis, the mechanisms of associated hepatic insulin resistance may not be necessarily the same at the molecular level. Recent studies have highlighted ER stress as an important mechanism integrating various pathways leading to insulin resistance during obesity. Previous studies have shown the involvement of the PERK/eIF2a and IRE1/XBP1 arms of the ER stress signaling pathways in hepatic steatosis and insulin resistance. In agreement with this, these two arms of ER stress signaling were significantly activated in response to HFru feeding. However, we did not detect any significant changes in ATF6, p-PERK, p-IRE1, p-eIF2a, or XBP1 splicing, after one. week of HFat feeding when hepatic steatosis and insulin resistance were clearly present. As ER stress can be triggered by the overload of newly synthesised unfolded proteins, the observed ER stress in this study may well result from the marked increases in lipogenic enzymes, given that high carbohydrate has been demonstrated to upregulate lipogenic enzymes via the actions of SREBP-1c and ChREBP. On the other hand, recent data have also indicated that ER stress may be able to directly promote lipogenesis. Of particular interest is the IRE1/XBP1 branch, which is found to be activated during elevated DNL in the present study. XBP1 is a nuclear transcriptional factor that can bind to the promoter regions of ACC and SCD-1 to increase lipogenesis. XBP1 can also directly interact with the regulatory subunit of PI3K, p85a, in.. the insulin signaling pathway to facilitate its transcriptional activity on genes involved in lipogenesis. It is possible that XBP-1 may interact with SREBP-1c which serves as a crosstalk point between ER stress and lipogenesis. However, further studies are needed to dissect the causal relationship among ER stress signaling pathways, lipogenesis and insulin resistance, as additional players in ER stress might be involved. In summary, the present study showed that the involvement of ER stress pathways in the development of hepatic steatosis and insulin resistance is induced only by dietary HFru but not by HFat feeding, suggesting that ER stress is involved in DNL per se NU7441 web rather than resulting from hepatic steatosis. Neither JNK nor IKK is required for the ER stress-induced insulin resistance as previously suggested in genetic models of obesity. Our data also indicated that mitochondrial dysfunction is unlikely to be a primary cause of hepatic steatosis and insulin resistance induced by HFru or HFat feeding. As insulin resistance is known to be multifactorial, our studies in these two nutritional models provide new insight into the potential role of different lipid metabolic pathways linking to hepatic steatosis and insulin resistance. Supporting Information ~~ Phosphatidylcholine is an essential phospholipid in eukaryotes, where it is a critical structural component of cell membrane, and plays key roles in signaling pathways. In contrast, only 10% of prokaryotes synthesize PC, with a higher frequency in bacterial symbionts and pathogens. In bacteria that produce PC, synthesis occurs mainly using two pathways: the Pmt- and Pcs-dependent pathways. The Pmt pathway, which is also conserved

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