Equally, there is quite a thorough literature on epigenetic influences in the inflammatory process

o forms of the protein were detected in Western blots of endogenous and adenoviral overexpressed GDE1, which is likely be due to variable glycosylation as previously documented. Its role in triglyceride metabolism has not been documented. Expression levels of TG biosynthetic pathways in the livers of Gde1-overexpressing mice were down-regulated, indicating that increased de novo MedChemExpress Vatalanib lipogenesis due to increased lipogenic gene expression is unlikely the cause of TG accumulation. Increased expression of Cd36 in Gde1-overexpressing livers raises the possibility that Cd36 acts as a mediator of the effect of Gde1 through its lipid transport activity. One of the products of the Gde1 enzymatic reaction is glycerol-3-phosphate, which can be converted to phosphatidate by glycerol-3-phosphate acyltransferase and subsequently dephosphorylated by the phosphatidate phosphatase lipin to form diacylglycerol. DAG can then be acylated by DGAT to form TG. We hypothesize that Gde1 affects the availability of glycerol-3-phosphate and modulates the flux of TG in the liver. The negative correlation of adipose Gde1 expression and hepatic TG may be due to a different role of glycerol-3-phosphate in the adipose tissue. Increased glycerol-3-phosphate production in the adipose tissue would promote FA re-esterification, leading to a decrease in FA release to the circulation. This reduction in FA supply to the liver may result in diminished TG synthesis. The opposite pattern of regulation of Gde1 implicates tissue-specific regulatory elements. Mouse ENCODE data showed that there are differences in DNA hypersensitive sites in the gene region, suggesting that Hui et al. eLife 2015;4:e05607. DOI: 10.7554/eLife.05607 16 of 28 Research article there may be differences in DNA accessibility and transcription factor binding in the liver and adipose tissue. The candidate genes under the chromosome 9 locus are likely to affect hepatic TG content via an insulin-dependent manner as the peak of association was diminished by co-mapping with obesity or insulin resistance. Insulin is a key hormone that drives lipogenesis and hepatic steatosis is often accompanied by hepatic insulin resistance. Our data showed that hepatic TG load has a robust association with plasma insulin levels and HOMA-IR. Impaired insulin signaling in the liver leads to the failure of insulin to suppress gluconeogenesis through the FoxO1 pathway, leading to hyperglycemia and ultimately diabetes. Paradoxically, insulinstimulated hepatic lipogenesis through SREBP-1c induction is not impaired in steatosis-associated insulin resistant livers. This selective insulin resistance leads to increased production of lipids and steatosis. The chromosome 3 signal was not affected by conditioning on percentage body fat or HOMA-IR, suggesting that the causal gene determining hepatic TG content at this locus are unlikely to be mediated by pathways involving body fat or insulin sensitivity. Our observed enrichment of mitochondrial genes in steatotic livers suggests that disrupted mitochondrial bioenergetics may play a role in NAFLD pathobiology. This is in accordance with finding that chronic consumption of a HF diet-induced NAFLD with PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19826048 reduced mitochondrial oxidation and increased ROS production. Obesity-induced steatosis has also been linked to decreased hepatic ATP synthesis. These findings highlighted the importance of mitochondrial function in the pathogenesis of NAFLD. Variations in mitochondrial capacity and activity may con