Objective Liver-enriched transcription factor CREBH regulates plasma triglyceride clearance by inducing lipoprotein lipase (LPL) co-factors such as apolipoprotein A-IV (apoA-IV), apoA-V, and apoC-II. CREBH also regulates apoA-I transcription. This study aims to determine whether CREBH has a role in lipoprotein metabolism and development of atherosclerosis. Approach and Results CREBH-deficient Creb3l3−/− mice were bred with Ldlr−/− mice creating Ldlr−/− Creb3l3−/− double knockout mice. Mice were fed on a high-fat and high-sucrose western diet (WD) for 20 weeks. We showed that CREBH deletion in Ldlr−/− mice increased VLDL-associated TG and cholesterol levels, consistent with the impairment of LPL-mediated TG clearance in these mice. In contrast, HDL cholesterol levels were decreased in CREBH-deficient mice, which was associated with decreased production of apoA-I from the liver. The results indicate that CREBH directly activated Apoa1 gene transcription. Accompanied by the worsened atherogenic lipid profile, Ldlr−/− Creb3l3−/− mice developed significantly more atherosclerotic lesions in the aortas than Ldlr−/− mice. Conclusions We identified CREBH as an important regulator of lipoprotein metabolism, and suggest that increasing hepatic CREBH activity may be a novel strategy for prevention and treatment of atherosclerosis.
Aim The hormonally controlled mobilization and release of fatty acids from adipocytes into the circulation is an important physiological process required for energy homeostasis. While uptake of fatty acids by adipocytes has been suggested to be predominantly protein-mediated, it is unclear whether the efflux of fatty acids also requires membrane proteins. Methods We used fluorescent fatty acid efflux assays and colorimetric assays for free fatty acids and glycerol to identify inhibitors with effects on fatty acid efflux, but not lipolysis, in 3T3-L1 adipocytes. We assessed the effect of these inhibitors on a fibroblast-based cell line expressing fatty acid transport protein 1, hormone-sensitive lipase, and perilipin, that presumably lacks adipocyte-speicific proteins for fatty acid efflux. Results We identified DIDS as an inhibitor of fatty acid efflux that did not impair lipolysis or the cellular exit of glycerol, but lead to an accumulation of intracellular fatty acids. In contrast, fatty acid efflux by the reconstituted cellular model for fatty acid efflux was responsive to lipolytic stimuli, but insensitive to DIDS inhibition. Conclusion We propose that adipocytes specifically express an as yet unidentified DIDS sensitive protein that enhances the efflux of fatty acids and therefore may lead to novel treatment approaches for obesity-related disorders characterized by abnormal lipid fluxes and ectopic triglyceride accumulation.
We investigated hypolipidemic mechanism of Melissa officinalis essential oil (MOEO). The major compound in MOEO was geranial (65%, w/w), quantified with GC/MS. After 2‐week feeding (0.0125 mg MOEO/mouse/day), plasma triglyceride levels were significantly reduced (−32%, P<0.05) in human apoE2 transgenic mice. Mouse hepatic transcriptome profiling with oligonucleotide microarray showed that fatty acid synthesis and β‐oxidation pathways were significantly altered. The rate of β‐oxidation, quantified with [1‐14C]palmitate, was not changed with MOEO in HepG2 cells, however, the expressions of SREBP‐1c and its target genes in the fatty acid synthesis including ACC2, FAS, and SCD1 were reduced in mouse livers assessed by quantitative PCR. The nuclear SREBP‐1c was reduced as well (−30%, P<.05). Chromatin immunoprecipitation results suggested that the bindings of PCAF, a coactivator of SREBP‐1c, and its H3K14 acetylation on the promoter of ACC2 (−9% for H3K14ac and −21% for PCAF binding) and FAS (−37% for H3K14ac and −10% for PCAF) were reduced. These suggest that MOEO may reduce plasma triglyceride levels by multiple mechanisms. The reduction of SREBP‐1c and its target gene expressions, decreasing nuclear translocation of SREBP‐1c, and the epigenetic down‐regulation of genes in fatty acid synthesis may result in net hypotriglyceridemic effects.
Plantago asiatica is a commonly used folk medicine in Eastern Asia and its essential oils have various bioactive compounds. Previously, we have showed that Plantago asiatica essential oils (PAEO) have hypolipidemic effects. Since compound A(82.6%) was a major component in the PAEO, we further examined hypolipidemic effects of compound A as well as the PAEO in diet‐induced obese mice. Mice (C57BL/6CrSlc) were fed a high fat diet for 5 weeks and then compound A and the PAEO were orally administered for 6 weeks under high fat diet. The PAEO and the compound A feeding significantly reduced plasma total cholesterol and triglyceride levels after 3 and 6 weeks, respectively, compared with the controls. Compound A reduced plasma cholesterol concentrations by approximately 20%. We investigated the effects of the PAEO and compound A on the expression of cholesterol metabolism genes. The expression of the HMG‐CoA reductase, assessed by RT‐PCR, was significantly reduced by 50% in the livers of compound A‐fed mice compared with the control livers after 6 weeks. Our data suggest that compound A, a major compound in the PAEO, may exert hypocholesterolaemic effects by downregulation of the HMG‐CoA reductase expression in diet‐induced obese mouse.
The effects of the lemon balm essential oils (LBEO) in the db/db mice were examined. Mice were divided into four groups and the LBEO was orally administered for 6 weeks: saline, control; 0.15mg/d, LBEO1; 0.05mg/d, LBEO2; 0.0125mg/d, LBEO3. The LBEO showed biphasic effects on plasma glucose levels; the low level feeding was hypoglycemic but the medium and the high levels exerted hyperglycemic effects. The LBEO3 group showed reduced fasting glucose (65%, P<0.05) and triglyceride concentrations compared with the controls. Glucose tolerance, assessed by oral glucose tolerance test, was improved in this group accordingly. However, in the LBEO1 and the LBEO2 groups, glucose tolerance was worsened according to the elevated fasting glucose levels compared with the controls (33% and 27% elevation in the LBEO1 and the LBEO2, respectively P<0.05). Plasma GOT and GPT levels were elevated in these groups as well. The hypoglycemic mechanism of low level feeding of the LBEO was further investigated with quantifying the expression of the glucose metabolism genes by real time PCR. The glucokinase and the GLUT 4 gene expressions were significantly upregulated, however, the expression of glucose‐6‐phosphase and phosphoenolpyruvate carboxykinase were downregulated in the mouse livers of the LBEO3 group. The results suggest that the LBEO may be hypoglycemic when administered at low concentration. These effects may be due to the enhanced glucose uptake and the inhibition of gluconeogenesis in the livers.
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