ARF , which was encoded by the Cdkn2a/INK4A locus. Thus, 3pK is a candidate regulator of phosphorylation-dependent PcG/chromatin interaction. We speculate that phosphorylation may not only affect chromatin association but, in addition, the function of individual complex members. Our findings linked for the first time MAPK signaling pathways to the Polycomb transcriptional memory system. This suggests a novel mechanism by which a silenced gene status can be modulated and implicates PcGmediated repression as a dynamically controlled process.

There is controversy over the extent to which fatty acids (FAs) derived from plasma free FAs (FFAs)

CD36 (fatty acid translocase) is involved in highaffinity peripheral fatty acid uptake. Mice lacking CD36 exhibit increased plasma free fatty acid and triglyceride (TG) levels and decreased glucose levels. Studies in spontaneous hypertensive rats lacking functional CD36 link CD36 to the insulin-resistance syndrome. To clarify the relationship between CD36 and insulin sensitivity in more detail, we determined insulin-mediated whole-body and tissue-specific glucose uptake in CD36-deficient (CD36 ؊ / ؊ ) mice. Insulinmediated whole-body and tissue-specific glucose uptake was measured by D -[ 3 H]glucose and 2-deoxy-D -[1-3 H]glucose during hyperinsulinemic clamp in CD36 ؊ / ؊ and wild-type control littermates (CD36 ؉ / ؉ ) mice. Whole-body and muscle-specific insulin-mediated glucose uptake was significantly higher in CD36 ؊ / ؊ compared with CD36 ؉ / ؉ mice. In contrast, insulin completely failed to suppress endogenous glucose production in CD36 ؊ / ؊ mice compared with a 40% reduction in CD36 ؉ / ؉ mice. This insulin-resistant state of the liver was associated with increased hepatic TG content in CD36 ؊ / ؊ mice compared with CD36 ؉ / ؉ mice (110.9 ؎ 12.0 and 68.9 ؎ 13.6 g TG/mg protein, respectively). Moreover, hepatic activation of protein kinase B by insulin, measured by Western blot, was reduced by 54%. Our results show a dissociation between increased muscle and decreased liver insulin sensitivity in CD36 ؊ / ؊ mice.

To study the role of apoC1 in lipoprotein metabolism, we have generated transgenic mice expressing the human APOC1 gene. On a sucrose-rich diet, male transgenic mice with high APOC1 expression in the liver showed elevated levels of serum cholesterol and triglyceride compared with control mice (5.7 Ϯ 0.7 and 3.3 Ϯ 2.1 vs. 2.7 Ϯ 0.1 and 0.4 Ϯ 0.1 mmol/liter, respectively). These elevated levels were mainly confined to the VLDL fraction. Female APOC1 transgenic mice showed less pronounced elevated serum lipid levels. In vivo VLDL turnover studies revealed that, in hyperlipidemic APOC1 transgenic mice, VLDL particles are cleared less efficiently from the circulation as compared with control mice. No differences were observed in the hepatic production and extrahepatic lipolysis of VLDL-triglyceride. Also, VLDL isolated from control and APOC1 transgenic mice were found to be equally good substrates for bovine lipoprotein lipase in vitro. These data indicate that the hyperlipidemia in APOC1 transgenic mice results primarily from impaired hepatic VLDL particle clearance, rather than a defect in the hydrolysis of VLDL-triglyceride.To

In patients with type 2 diabetes, a strong correlation between accumulation of intramuscular triclycerides (TGs) and insulin resistance has been found. The aim of the present study was to determine whether there is a causal relation between intramuscular TG accumulation and insulin sensitivity. Therefore, in mice with musclespecific overexpression of human lipoprotein lipase (LPL) and control mice, muscle TG content was measured in combination with glucose uptake in vivo, under hyperinsulinemic-euglycemic conditions. Overexpression of LPL in muscle resulted in accumulation of TGs in skeletal muscle (85.5 ؎ 33.3 vs. 25.7 ؎ 23.1 mol/g tissue in LPL and control mice, respectively; P < 0.05). During the hyperinsulinemic clamp study, there were no differences in plasma glucose, insulin, and FFA concentrations between the two groups. Moreover, wholebody, as well as skeletal muscle, insulin-mediated glucose uptake did not differ between LPL-overexpressing and wild-type mice. Surprisingly, whole-body glucose oxidation was decreased by ϳ60% (P < 0.05), whereas nonoxidative glucose disposal was increased by ϳ50% (P < 0.05) in LPL-overexpressing versus control mice. In conclusion, overexpression of human LPL in muscle increases intramuscular TG accumulation, but does not affect whole-body or muscle-specific insulinmediated uptake, findings that argue against a simple causal relation between intramuscular TG content and insulin resistance.