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How omega-3 and omega-6 polyunsaturated fatty acids (PUFAs) lower plasma lipid levels is incompletely understood. We previously showed that marine omega-3 PUFAs (docosahexaenoic acid [DHA] and eicosapentaenoic acid) stimulate a novel pathway, post-ER presecretory proteolysis (PERPP), that degrades apolipoprotein B100 (ApoB100), thereby reducing lipoprotein secretion from liver cells. To identify signals stimulating PERPP, we examined known actions of omega-3 PUFA. In rat hepatoma or primary rodent hepatocytes incubated with omega-3 PUFA, cotreatment with the iron chelator desferrioxamine, an inhibitor of iron-dependent lipid peroxidation, or vitamin E, a lipid antioxidant, suppressed increases in thiobarbituric acid-reactive substances (TBARSs; a measure of lipid peroxidation products) and restored ApoB100 recovery and VLDL secretion. Moreover, omega-6 and nonmarine omega-3 PUFA, also prone to peroxidation, increased ApoB100 degradation via intracellular induction of TBARSs. Even without added fatty acids, degradation of ApoB100 in primary hepatocytes was blocked by desferrioxamine or antioxidant cotreatment. To extend these results in vivo, mice were infused with DHA, which increased hepatic TBARSs and reduced VLDL-ApoB100 secretion. These results establish a novel link between lipid peroxidation and oxidant stress with ApoB100 degradation via PERPP, and may be relevant to the hypolipidemic actions of dietary PUFAs, the basal regulation of ApoB100 secretion, and hyperlipidemias arising from ApoB100 overproduction.

Nucleotide binding site (NBS)-leucine-rich repeat (LRR) genes belong to the largest class of disease-resistance gene super groups in plants, and their intra- or interspecies nucleotide variations have been studied extensively to understand their evolution and function. However, little is known about the evolutionary patterns of their copy numbers in related species. Here, 129, 245, 239 and 508 NBSs were identified in maize, sorghum, brachypodium and rice, respectively, suggesting considerable variations of these genes. Based on phylogenetic relationships from a total of 496 ancestral branches of grass NBS families, three gene number variation patterns were categorized: conserved, sharing two or more species, and species-specific. Notably, the species-specific NBS branches are dominant (71.6%), while there is only a small percentage (3.83%) of conserved families. In contrast, the conserved families are dominant in 51 randomly selected house-keeping genes (96.1%). The opposite patterns between NBS and the other gene groups suggest that natural selection is responsible for the drastic number variation of NBS genes. The rapid expansion and/or contraction may be a fundamentally important strategy for a species to adapt to the quickly changing species-specific pathogen spectrum. In addition, the small proportion of conserved NBSs suggests that the loss of NBSs may be a general tendency in grass species.

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Insulin-resistant apoB/BATless mice have hypertriglyceridemia because of increased assembly and secretion of very low density apolipoprotein B (apoB) and triglycerides compared with mice expressing only apoB (Siri, P., Candela, N., Ko, C., Zhang, Y., Eusufzai, S., Ginsberg, H. N., and Huang, L. S. (2001) J. Biol. Chem. 276, 46064 -46072). Despite increased very low density lipoprotein secretion, apoB/BATless mice have fatty livers. We found that hepatic mRNA levels of key lipogenic enzymes, acetyl-CoA carboxylase, fatty-acid synthase, and stearoyl-CoA desaturase-1 were increased in apoB/BATless mice compared with levels in apoB mice, suggesting increased lipogenesis in apoB/BATless mice. This was confirmed by determining incorporation of tritiated water into fatty acids. Neither the hepatic mRNA of the lipogenic transcription factor, SREBP-1c (sterol-response element-binding protein 1c), nor the nuclear levels of the mature form of SREBP-1 protein were elevated in apoB/BATless mice. By contrast, hepatic levels of peroxisomal proliferator-activated receptor 2 (PPAR␥2) mRNA and protein were specifically increased in apoB/BATless mice, as were hepatic mRNA levels of two targets of PPAR␥, CD36 and aP2. Treatment of apoB/BATless mice for 4 weeks with intraperitoneal injections of a PPAR␥ antisense oligonucleotide resulted in dramatic reductions of both PPAR␥1 and PPAR␥2 mRNA, PPAR␥2 protein, and mRNA levels of fatty-acid synthase and acetyl-CoA carboxylase. These changes were associated with decreased hepatic de novo lipogenesis and hepatic triglyceride concentrations. We conclude that hepatic steatosis in apoB/ BATless mice is associated with elevated rates of hepatic lipogenesis that are linked directly to increased hepatic expression of PPAR␥2. The mechanism whereby hepatic Ppar␥2 gene expression is increased and how PPAR␥2 stimulates lipogenesis is under investigation.We reported previously that apoB/BATless mice, a model generated by crossing mice expressing human apolipoprotein B (apoB) 3 (1) with mice lacking brown adipose tissue (BATless) (2), have hypertriglyceridemia and hypercholesterolemia because of a 2-3-fold increase in the secretion of very low density lipoprotein (VLDL) apoB and triglycerides (TG) relative to mice expressing apoB only (3). Similar levels of apoB mRNA in the livers of apoB and apoB/BATless mice indicated that the differences in apoB secretion resulted from differences in posttranscriptional regulation of VLDL assembly and secretion (4). There were no differences in hepatic levels of microsomal triglyceride transfer protein mRNA (3), a critical factor in the early co-and post-translational regulation of apoB-containing lipoprotein secretion (5). Low density lipoprotein receptor mRNA levels in liver were higher in apoB/BATless compared with apoB mice (3), indicating that increased apoB secretion in apoB/BATless mice did not result from reduced interactions of the low density lipoprotein receptor with nascent apoB lipoproteins (6).Associated with a rising prevalence of obesity and insuli...