Prp19p is an integral component of the heteromeric protein complex (the NineTeen complex) in the nucleus, and it is essential for the structural integrity of NineTeen complex and its subsequent activation of the spliceosome. We identified Prp19p, which has never been reported in relation to any function outside of the nucleus, as a member of proteins associated with lipid droplets. Down-regulation of Prp19p expression with RNA interference in 3T3-L1 cells repressed lipid droplet formation with the reduction in the level of expression of perilipin and S3-12. The levels of expression of SCD1 (stearoyl-CoA desaturase-1), DGAT-1 (acyl-CoA diacylglycerol acyltransferase-1), and glycerol-3-phosphate acyltransferase were also reduced in Prp19p down-regulated cells, and a significant decrease in triglycerides was observed. Unlike perilipin, which is one of the most extensively studied lipid droplet-associated proteins, Prp19p is not essential for cAMP-and hormone-sensitive lipasedependent lipolysis pathways, even though Prp19p is a component of the lipid droplet phospholipid monolayer, and downregulation of Prp19p represses fat accretion significantly. These results suggest that Prp19p or Prp19-interacting proteins during lipid droplet biogenesis in adipocytes may be considered as another class of potential targets for attacking obesity and obesity-related problems.Lipid droplets are subcellular organelles that function as major energy depots by storing neutral lipids, mainly triacylglycerols (1, 2). Therefore, the biogenesis of a lipid droplet is central to whole body energy homeostasis. In addition to their function as energy depots, lipid droplets appear to have important roles in lipid trafficking in adipocytes, cell signaling, and several important human diseases (3-7). It is thus important to understand the mechanism of deposition and mobilization of cellular neutral lipids. Although the mechanisms of lipid droplet biogenesis are still not entirely clear, it is expected that a set of proteins involved in lipid droplet biogenesis could comprise effective targets for the regulation of the whole body energy homeostasis. Lipid droplets are surrounded by a phospholipid monolayer into which many proteins are embedded (8). These surface proteins on adipocyte lipid droplets include structural proteins, such as PAT (perilripin/ADRP/TIP47) family proteins, S3-12, vimentin, and caveolin-1, and enzymes involved in many aspects of lipid metabolism, such as hormone-sensitive lipase (HSL)-, acyl-CoA synthetase-, lanosterol synthase-, CGI-58-, and NAD(P)-dependent steroid dehydrogenase-like protein and members of the Rab family of GTPases. Some of these lipid droplet-associated proteins are reported to play important roles in the functions of the lipid droplets (7, 9 -13).In this study, in order to explore proteins that are involved in lipid droplet biogenesis, we investigated the protein composition of lipid droplets isolated from cultured 3T3-L1 adipocytes, and we identified several more lipid droplet-associated proteins using ...
Genistein is one of the most abundant isoflavones in soy. The effects of genistein on cholesterol synthesis and fatty acid oxidation have been well documented, but the effect of genistein on fatty acid synthesis remains unclear. Thus, we investigated the effect of genistein on fatty acid synthase (FAS) expressions in HepG2 cells. In HepG2 cells treated with 10 micromol/L genistein, mRNA and protein expressions of FAS, as well as FAS activity, were significantly decreased. The promoter region of FAS contains binding sites for the transcription factor called sterol regulated element binding protein 1 (SREBP-1); SREBP-1 must be processed by site-1 (S1P) and site-2 proteases to be activated. We also investigated the effects of genistein on S1P, SREBP-1 expression, and subsequent SREBP-1 processing by S1P in HepG2 cells. Genistein reduced the expression of S1P and the processing of SREBP-1 but did not change the expression of SREBP-1 mRNA. SREBP-1 is also a transcription factor for lipogenic genes, such as stearoyl coenzyme-A desaturase1 (SCD1), glycerol-3-phosphate acyltransferase (GPAT), and acetyl-CoA carboxylase (ACC)1, and ACC2. Genistein also significantly inhibited the expression of these lipogenic genes. Thus, genistein treatment of HepG2 cells decreased the expression of lipogenic genes such as FAS, SCD1, GPAT, and ACC, which is, at least in part, mediated through the downregulation of S1P expression and subsequent SREBP-1 proteolytic cleavage.
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