The tumor necrosis factor‐α (TNF‐α) expression has been reported to be largely dependent on the size of adipocytes. We herein investigated the gene regulation of diacylglycerol O ‐acyltransferase (DGAT) in order to clarify the mechanism of TNF‐α expression induced in large adipocytes. 3T3‐L1 cells were cultured in the presence of 5 mM or 25 mM glucose to generate adipocytes from which the triglyceride content differs. The expression of TNF‐α, DGAT1, and DGAT2 were upregulated in adipocytes cultured with 25 mM glucose. Furthermore, knockdown of DGAT1 gene significantly inhibited the TNF‐α expression. Finally, the DGAT1 expression levels were closely related to the TNF‐α level in 3T3‐L1 adipocytes.
There is a growing body of evidence that the formation and accumulation of advanced glycation end products (AGE) have been known to progress under diabetic conditions, thereby being involved in diabetic vascular complications. Further, we, along with others, have recently found AGE could disturb insulin actions in cultured adipocytes and skeletal muscles. However, the pathological role of AGE in insulin resistance in vivo is not fully understood. Therefore, in this study, we examined whether pyridoxamine, an inhibitor of AGE formation could ameliorate insulin resistance in KK-Ay mice, a model animal of obese, type 2 diabetes. Fasting blood glucose, serum levels of insulin and AGE in KK-Ay mice were elevated as the mice got older (from 5 weeks old to 15 weeks old). Serum levels of AGE were positively correlated with insulin (R2=0.3956, P=0.002) in KK-Ay mice. Administration of pyridoxamine dose-dependently decreased fasting insulin levels and improved insulin sensitivity in KK-Ay mice of 10 weeks old, although it did not affect fasting blood glucose levels. Our present study suggests the involvement of AGE in insulin resistance in KK-Ay mice. Inhibition of AGE formation may be a novel therapeutic target for improving insulin resistance in diabetes with obesity. Keywords: AGE, insulin resistance, diabetes
Auto-transplantation of adipose tissue is commonly used for the treatment of tissue defects in plastic surgery. The survival of the transplanted adipose tissue is not always constant, and one of reasons is the accelerated apoptosis of the implanted preadipocytes. We have recently established highly homogeneous preadipocytes, named ccdPAs. The aim of the current study was to evaluate the regulation of the potency of platelet-rich plasma (PRP) on the apoptosis of ccdPAs in vitro. PRP stimulated the proliferation of the preadipocytes in a dose-dependent manner, and the stimulatory activity of 2% PRP was significantly higher than that of 2% FBS or 2% platelet-poor plasma (PPP). The presence of 2% PRP significantly inhibited serum starvation- or TNF-α/cycloheximide-induced apoptosis in comparison to 2% FBS or 2% PPP. DAPK1 and Bcl-2-interacting mediator of cell death (BIM) mRNAs were reduced in the preadipocytes cultured with 2% PRP in comparison to those cultured in 2% FBS. The gene expression levels were significantly higher in cells cultured without serum in comparison to cells cultured with 2% FBS, and the levels in the cells with 2% PRP were reduced to 5-10% of those in the cells without serum. These results indicated that ccdPAs exhibit anti-apoptotic activities, in addition to increased proliferation, when cultured in 2% PRP in comparison to the same concentration of FBS, and that this was accompanied with reduced levels of DAPK1 and BIM mRNA expression in in vitro culture. PRP may improve the outcome of transplantation of adipose tissue by enhancing the anti-apoptotic activities of the implanted preadipocytes.
To determine how lipoprotein lipase mass in the pre-heparin plasma is affected by body fat distribution, which is known to be closely related to lipid disorder, either directly or through insulin resistance.A total of 57 subjects consisting of 50 hyperlipidemic and 7 normolipidemic subjects (age 54 +/- IIy; 31 men, 26 women; body mass index 24+/- 2.5 kg/m2; serum total cholesterol 6.4+/-1.5 mmol/l; triglycerides, 2.4 +/- 1.7 mmol/l; HDL-cholesterol 1.3 +/- 0.5 mmol/l) were enrolled.We investigated the correlation between pre-heparin plasma LPL mass and intra-abdominal visceral fat area (or subcutaneous fat area) evaluated by computed tomography, and serum lipids and lipoproteins.Pre-heparin plasma LPL mass correlated inversely against intra-abdominal visceral fat area (r = - 0.51, p < 0.0001) and body mass index (r = - 0.46, p = 0.0003), but did not show any significant correlation with subcutaneous fat area. Pre-heparin plasma LPL mass had a positive correlation with serum high density lipoprotein cholesterol (r = 0.45, p = 0.0004) and a negative correlation against serum triglycerides (r = - 0.48, p = 0.0002).Pre-heparin plasma LPL mass is closely associated with intra-abdominal fat distribution, and the measurement of its value gives useful information concerning metabolic disorder.
Not all genetic factors predisposing phenotypic features of dyslipidemia have been identified. We studied the association between the low density lipoprotein-related protein 2 gene (LRP2) and levels of plasma total cholesterol (T-Cho) and LDL-cholesterol (LDL-C) among 352 adults in Japan.Subjects were obtained from among participants in a cohort study that was carried out with health-check screening in an area of east-central Japan. We selected 352 individuals whose LDL-C levels were higher than 140 mg/dL from the initially screened 22,228 people. We assessed the relation between plasma cholesterol levels and single-nucleotide polymorphisms (SNPs) in the LRP2 gene.We identified significant correlations between plasma cholesterol levels and two of 19 examined SNPs in LRP2, c.+193826T/C and IVS55 - 147A/G. In particular, the association of c.+193826T/C with the T-Cho level was prominent (p=0.003), showing a co-dominant effect of the minor C-allele on lowering T-Cho and LDL-C levels: for 24 homozygous C-allele carriers, T-Cho=240.7 +/- 24.2 mg/dL and LDL-C=166.1 +/- 21.0 mg/dL); for 130 heterozygous carriers, 248.5 +/- 23.5 mg/dL and 166.6 +/- 19.3 mg/dL; and for 196 homozygous T-allele carriers, 253.9 +/- 23.5 mg/dL and 172.0 +/- 21.0 mg/dL. Linkage disequilibrium (LD) analyses based on 19 selected SNPs showed that c.+193826T/C and IVS55 - 147A/G were in tight LD and that both were located in an LD block covering the genomic sequence from exon 55 to exon 61.We confirm the association between LRP2 and levels of T-Cho and LDL-C in human plasma. The results suggest that genetic variations in LRP2 are important factors affecting lipoprotein phenotypes of patients with hypercholesterolemia.
Intimal smooth muscle cells (SMCs) play an important role in the vasculitis caused by Kawasaki disease (KD). Lipoprotein receptor 11 (LR11) is a member of the low-density lipoprotein receptor family, which is expressed markedly in intimal vascular SMCs and secreted in a soluble form (sLR11). sLR11 has been recently identified as a potential vascular lesion biomarker. sLR11 is reportedly elevated in patients with coronary artery lesions long after KD, but there is no description of sLR11 in acute KD. Our aim was to determine the sLR11 dynamics in acute KD and to assess its usefulness as a biomarker.
Lecithin: cholesterol acyltransferase (LCAT) is the enzyme that catalyze the esterification of free cholesterol in plasma proteins. The functional abnormalities of LCAT are known to cause two diseases characterized by severe corneal opacity; familial LCAT deficiency that is accompanied with anemia and frequently, though not invariably, renal failure, and fish eye disease (FED) without any other severe symptoms. Notably, it has been shown that the clinical symptoms and biochemical features are highly variable in each patient with the diseases. Recent genetic studies on the cases of LCAT deficiency or FED revealed both diseases to be caused by respective mutations of the LCAT gene. These findings suggest the abnormal or defective LCAT by each gene mutation underlies the heterogeneity in the biochemical and, possibly, clinical characteristics observed in LCAT deficiency and FED.
Although the Japan Atherosclerosis Society guideline for the diagnosis and prevention of atherosclerosis cardiovascular diseases for the Japanese population provides targets for low-density lipoprotein (LDL) cholesterol, triglycerides, and high-density lipoprotein (HDL) cholesterol to prevent cardiovascular disease in patients with dyslipidemia, there is no guideline specifically targeting the treatment of type IIb dyslipidemia, which is one of the most common types of dyslipidemia, along with type IIa and type IV dyslipidemia. Type IIb dyslipidemia is important because it sometimes accompanies atherogenic lipid profiles, such as small, dense LDL, remnants, low HDL cholesterolemia. It is also associated with type 2 diabetes mellitus, metabolic syndrome, and chronic kidney disease (CKD), and most patients with familial combined hyperlipidemia (FCHL) show this phenotype; therefore, it is assumed that patients with type IIb dyslipidemia have a high risk for cardiovascular disease. Thus, the management of type IIb dyslipidemia is very important for the prevention of cardiovascular disease, so we have attempted to provide a guideline for the management of type IIb dyslipidemia.
