The extent of translational control of gene expression in mammalian tissues remains largely unknown. Here we perform genome-wide RNA sequencing and ribosome profiling in heart and liver tissues to investigate strain-specific translational regulation in the spontaneously hypertensive rat (SHR/Ola). For the most part, transcriptional variation is equally apparent at the translational level and there is limited evidence of translational buffering. Remarkably, we observe hundreds of strain-specific differences in translation, almost doubling the number of differentially expressed genes. The integration of genetic, transcriptional and translational data sets reveals distinct signatures in 3′UTR variation, RNA-binding protein motifs and miRNA expression associated with translational regulation of gene expression. We show that a large number of genes associated with heart and liver traits in human genome-wide association studies are primarily translationally regulated. Capturing interindividual differences in the translated genome will lead to new insights into the genes and regulatory pathways underlying disease phenotypes.
Major controversy exists as to whether increased C-reactive protein (CRP) contributes to individual components of the metabolic syndrome or is just a secondary response to inflammatory disease processes. We measured blood pressure and metabolic phenotypes in spontaneously hypertensive rats (SHR) in which we transgenically expressed human CRP in liver under control of the apoE promoter. In SHR transgenic rats, serum levels of human CRP approximated the endogenous levels of CRP normally found in the rat. Systolic and diastolic blood pressures measured by telemetry were 10–15 mmHg greater in transgenic SHR expressing human CRP than in SHR controls (P<0.01). During oral glucose tolerance testing, transgenic SHR exhibited hyperinsulinemia compared to controls (insulin area under the curve 36±7 versus 8±2 nmol/L/2h, respectively, P<0.05). Transgenic SHR also exhibited resistance to insulin stimulated glycogenesis in skeletal muscle (174±18 versus 278±32 nmol glucose/g/2h, P<0.05), hypertriglyceridemia (0.84±0.05 versus 0.64±0.03 mmol/L, P<0.05), reduced serum adiponectin (2.4±0.3 versus 4.3±0.6 mmol/L, P<0.05), and microalbuminuria (200±35 versus 26±5 mg albumin/g creatinine, respectively, P<0.001). Transgenic SHR had evidence of inflammation and oxidative tissue damage with increased serum levels of interleukin 6 (IL6) (36.4±5.2 versus 18±1.7 pg/ml, P<0.005) and increased hepatic and renal TBARS (1.2±0.09 versus 0.8±0.07 and 1.5±0.1 versus 1.1±0.05 nM/mg protein, respectively, P<0.01), suggesting that oxidative stress may be mediating adverse effects of increased human CRP. These findings are consistent with the hypothesis that increased CRP is more than just a marker of inflammation and can directly promote multiple features of the metabolic syndrome.
Fatty acid esters of hydroxy fatty acids (FAHFAs) are lipid mediators with promising antidiabetic and anti-inflammatory properties that are formed in white adipose tissue (WAT) via de novo lipogenesis, but their biosynthetic enzymes are unknown. Using a combination of lipidomics in WAT, quantitative trait locus mapping, and correlation analyses in rat BXH/HXB recombinant inbred strains, as well as response to oxidative stress in murine models, we elucidated the potential pathway of biosynthesis of several FAHFAs. Comprehensive analysis of WAT samples identified ∼160 regioisomers, documenting the complexity of this lipid class. The linkage analysis highlighted several members of the nuclear factor, erythroid 2 like 2 ()-mediated antioxidant defense system (), lipid-handling proteins (), and the family of flavin containing monooxygenases () as the positional candidate genes. Transgenic expression of and deletion of genes resulted in reduction of palmitic acid ester of 9-hydroxystearic acid (9-PAHSA) and 11-PAHSA levels, while oxidative stress induced by an inhibitor of glutathione synthesis increased PAHSA levels nonspecifically. Our results indicate that the synthesis of FAHFAs via carbohydrate-responsive element-binding protein-driven de novo lipogenesis depends on the adaptive antioxidant system and suggest that FAHFAs may link activity of this system with insulin sensitivity in peripheral tissues.
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