Genetic assessment using whole-exome sequencing for a young hypertriglyceridemic patient with repeated acute pancreatitis.

Hypertriglyceridemia is caused not only by environmental factors but also by genetic factors. Severe hypertriglyceridemia is prone to complications of acute pancreatitis. Here, we report a whole-exome sequencing (WES) analysis for a young hypertriglyceridemic patient with recurrent acute pancreatitis and the patient's mother. A 28-year-old hypertriglyceridemic female was admitted to our hospital. At 23 years old, a health checkup clarified her hypertriglyceridemia. At the age of 26 and 27, she had repeated acute pancreatitis with severe hypertriglyceridemia (serum triglyceride level were 3,888 mg/dL and 12,080 mg/dL, respectively). The patient's BMI was 29.0 kg/m2, and blood samples under fibrate medication showed triglyceride 451 mg/dL and HbA1c 7.2%. Type V dyslipidemia became more apparent at postprandial state. The WES analysis showed that the patients had two heterozygous variants in Apolipoprotein A5 (APOA5) gene (p.G185C and p.V153M), a heterozygous variant in Apolipoprotein E (APOE) gene (p.R176C), three heterozygous variants in Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene (p.T1220I, p.R1453W and p.V470M). On the other hand, her mother, who had moderate hypertriglyceridemia without acute pancreatitis, had a heterozygous variant in APOA5 gene (p.G185C) and two heterozygous variants in CFTR gene (p.T1220I and p.V470M). These results suggest that the more severe pathology of the patient than her mother might be due to the possible compound heterozygous APOA5 variants, the heterozygous APOE variant, and the possible compound heterozygous CFTR variants. In this case, WES analyses were useful to evaluate not only the causative genes of hypertriglyceridemia (APOA5 and APOE) but also the genes involved in the development of acute pancreatitis (CFTR) simultaneously.

Regulation of secretion and enzymatic activity of lipoprotein lipase by C-mannosylation.

Lipoprotein lipase (LPL) is a crucial enzyme in lipid metabolism and transport, and its enzymatic deficiency causes metabolic disorders, such as hypertriglyceridemia. LPL has one predicted C-mannosylation site at Trp417. In this study, we demonstrated that LPL is C-mannosylated at Trp417 by mass spectrometry. Furthermore, by using wild-type and a C-mannosylation-defective mutant of LPL-overexpressing cell lines, we revealed that both secretion efficiency and enzymatic activity of C-mannosylation-defective mutant LPL were lower than those of wild-type. These data suggest the importance of C-mannosylation for LPL functions.

Metformin reduces circulating malondialdehyde-modified low-density lipoprotein in type 2 diabetes mellitus.

PURPOSE: Type 2 diabetes is known to be associated with increasing cardiovascular mortality. Malondialdehyde-modified LDL (MDA-LDL) is an oxidized LDL and is increased in patients with diabetes or hypertriglyceridemia. Elevated MDA-LDL has been reported to be a risk factor of atherosclerosis or cardiovascular disease. Sitagliptin is a dipeptidyl peptidase-4 inhibitor and a new class of hypoglycemic agents. In this study, the effects of increasing the dose of metformin and add-on sitagliptin on MDA-LDL were examined in type 2 diabetes patients. METHODS: Seventy patients with type 2 diabetes, inadequately controlled despite on-going treatment with metformin 500 mg/day, were enrolled in this randomized controlled trial. The patients received additional metformin (500 mg/day) or sitagliptin (50 mg/day) for 6 months, and changes in metabolic parameters including MDA-LDL were evaluated. RESULTS: After 6 months of treatment, add-on sitagliptin (n=35) improved fasting blood glucose (FBG) and hemoglobin A1c (HbA1c) to significantly greater extent than increasing the dose of metformin (n=35). There were no differences in total cholesterol and low-density lipoprotein cholesterol levels between two groups. MDA-LDL levels (mean ± S.E.) decreased significantly with increasing the dose of metformin (from 94.40 ± 6.35 to 77.83 ± 4.74 U/L, P < 0.005), but remained unchanged with add-on sitagliptin treatment (from 89.94 ± 5.59 to 98.46 ± 6.78 U/L, p > 0.05). Multiple linear regression analysis identified increasing the dose of metformin treatment as the only independent factor associated with decreased MDA-LDL (ß coefficient 0.367, P < 0.0119), and no significant correlation between change in MDA-LDL and fasting blood glucose or HbA1c. CONCLUSION: These results suggest that increasing the dose of metformin improves serum MDA-LDL levels in type 2 diabetes mellitus.

Evaluation of plasma vascular endothelial growth factor levels after intravitreal injection of ranibizumab and aflibercept for exudative age-related macular degeneration.

BACKGROUND: To evaluate the plasma vascular endothelial growth factor (VEGF) levels after one intravitreal injection of aflibercept or ranibizumab in patients with exudative age-related macular degeneration (AMD). METHODS: Twenty-four Japanese with exudative AMD, polypoidal choroidal vasculopathy, and retinal angiomatous proliferation were included. Fourteen patients received an intravitreal injection of aflibercept, and ten patients received an intravitreal injection of ranibizumab. Plasma VEGF levels were evaluated within 7 days before the intravitreal injections and 1 day, 1 week, and 1 month after the intravitreal injection. RESULTS: In the ranibizumab group, the mean plasma VEGF levels were 245.7 ± 233.4 pg/ml before the injection, 246.6 ± 304.8 pg/ml after 1 day, 217.8 ± 212.9 pg/ml after 1 week, and 260.0 ± 290.1 pg/ml after 1 month. The plasma VEGF levels did not decrease significantly in patients in the ranibizumab group at any time point. In the aflibercept group, the mean plasma VEGF levels were 280.0 ± 170.3 pg/ml before the intravitreal injection and 8.2 ± 12.9 pg/ml after 1 day, 9.1 ± 9.1 pg/ml after 1 week, and 41.9 ± 41.4 pg/ml after 1 month (p < 0.0001, vs before injection). CONCLUSION: Intravitreally injected aflibercept reduced plasma VEGF over at least 1 month. In contrast, intravitreal injection of ranibizumab did not cause a significant reduction in the plasma VEGF levels.

C5 variant is associated with decreased risk of coronary artery disease in outpatients with severe hypercholinesterasemia.

OBJECTIVE: Although the C5 variant of cholinesterase is known to be a cause of hypercholinesterasemia, the pathophysiological significance of the C5 variant and the C5 variant-related hypercholinesterasemia in cardiovascular diseases remain unclear. The present study aimed to clarify the pathophysiological significance of the C5 variant as a risk or protective factor for coronary artery disease (CAD) in patients with severe hypercholinesterasemia. METHODS: Severe hypercholinesterasemia was defined as serum cholinesterase (ChE) activity >= 450 IU/L (>= 2.0 SD). We screened 11,648 consecutive outpatients between 2005 and 2011 at Toho University, Sakura Medical Center. In patients with severe hypercholinesterasemia, phenotyping of the C5 variant was conducted using polyacrylamide gel electrophoresis and alpha-naphthyl butyrate staining. RESULTS: 157 subjects (1.4% of 11,648 outpatients screened) were diagnosed with severe hypercholinesterasemia (mean serum ChE activity 574 ± 109 IU/L), and the frequency of the C5 variant was 45.2%. Subjects with the C5 variant had higher age, lower body mass index, milder dyslipidemia and liver dysfunction, and lower rates of hypertension and CAD compared with subjects without the C5 variant. Multivariate logistic regression model demonstrated that the presence of C5 variant independently lowered the risk of CAD, with odds ratio 0.071 (95% confidence interval (CI) 0.007 - 0.763, p = 0.029). CONCLUSION: The prevalence of the C5 variant was relatively high, and the C5 variant is associated with decreased risk of CAD in outpatients with severe hypercholinesterasemia.

[Comparison of antioxidant capacities in serum and vitreous fluids of vitreoretinal diseases].

PURPOSE: To investigate serum antioxidant potential of patients with vitreoretinal diseases that require vitreous surgery and the antioxidant potential in vitreous fluids obtained intraoperatively. SUBJECTS AND METHODS: Twenty seven eyes of 27 patients who had undergone vitrectomy for macular edema associated with branch retinal vein occlusion (BRVO), proliferative diabetic retinopathy (PDR), macular hole (MH)/epiretinal membrane (ERM) at Toho University Sakura Medical Center were studied. The biological anti-oxidant potential (BAP), as an index of anti-oxidant potential of serum and vitreous fluid was measured using a free radical elective evaluator (FREE). RESULTS: The vitreous BAP levels (microEq/l) in the PDR group was 1843 +/- 402 and in the BRVO group, 2120 +/- 413. The BAP levels in the vitreous fluid of the PDR and BRVO were significantly lower than those of control subjects. The serum BAP levels (microEq/l) in the PDR group was 2307 +/- 51.9 and in the BRVO group, 2390 +/- 149. The serum BAP levels in the PDR group were significantly lower than those in the control group. Only in the PDR group, the serum BAP was significantly lower than the vitreous BAP. The vitreous BAP levels were significantly positively correlated with those of the serum. CONCLUSIONS: A difference was shown between the antioxidant potentials of the vitreous fluid and serum in the patients with PDR. Antioxidant potential in the eye had possibly declined in patients with ischemic vitreoretinal disease compared with other vitreoretinal diseases.

Tissue expression of Toll-like receptors 2 and 4 in sporadic human colorectal cancer.

BACKGROUND: Toll-like receptors (TLRs) play an important role in innate immunity by sensing a variety of pathogens and inducing acquired immunity. To test our hypothesis that dysregulation of innate immune responses acts to trigger carcinogenesis, we studied the expression of TLR2 and 4 in sporadic human colorectal cancer tissue. METHODS: In specimens of cancerous and noncancerous colorectal tissue obtained at surgery, mRNA expression levels of TLR2 and 4 were quantified by TaqMan real-time polymerase chain reaction and compared between the two types of tissue. To confirm TLR2 and TLR4 protein expression levels, immunohistochemical analysis was performed using the same samples. RESULTS: TLR2 mRNA expression was significantly higher in cancerous tissue than in noncancerous tissue, while TLR4 mRNA expression did not differ significantly. Immunohistochemical analysis revealed stronger staining for TLR2 in cancerous mucosal epithelial cells than in noncancerous tissue. Staining for TLR4 in the lamina propria of the mucosa was equally weakly positive in noncancerous tissue and cancerous tissue. This TLR-specific difference in expression suggested that such expression does not only reflect a local inflammatory response to cancer infiltration, i.e., if this was the case, both TLR2 and 4 expression would probably be up-regulated. Our results suggest that TLR2 expression might be involved in sporadic colorectal carcinogenesis, whereas TLR4 is not.

Alpha-synuclein in the cerebrospinal fluid differentiates synucleinopathies (Parkinson Disease, dementia with Lewy bodies, multiple system atrophy) from Alzheimer disease.

BACKGROUND: We examined the utility of quantification of α-synuclein (SNCA) in the cerebrospinal fluid (CSF) to differentiate patients with Alzheimer disease (AD), dementia with Lewy bodies (DLB), Parkinson disease (PD), and multiple system atrophy (MSA). METHODS: Thirty-seven patients were divided into 4 age-matched and sex-matched clinical groups: AD (n = 9), DLB (n = 6), PD (n = 11), and MSA (n = 11). Eleven subjects served as neurological disease controls. The total of 48 subjects included 27 men and 21 women, aged 66.5 ± 11.4 years. We performed a solid-phase sandwich enzyme-linked immunosorbent assay, which enables the sensitive quantification of CSF SNCA. RESULTS: In comparison with controls, CSF SNCA levels in AD were significantly higher (P < 0.05). CSF SNCA levels in PD (P < 0.001), DLB (P < 0.01), and MSA (P < 0.05) were all significantly lower than those in AD. However, CSF SNCA levels did not differ significantly among the 3 synucleinopathies. CONCLUSIONS: The results of the present study suggest that quantification of CSF SNCA helps in the differentiation of synucleinopathies (PD, DLB, and MSA) from AD. However, CSF SNCA levels did not differ significantly among the 3 synucleinopathies.

[Relation between cardio-ankle vascular index (Cavi) and preheparin serum lipoprotein lipase mass--effect of age adjustment].

Many risk factors for coronary arterial diseases have been reported. Lipoprotein lipase (LPL) mass in serum has been suggested to be a new risk factor, but remains to be proven. The cardio-ankle vascular index (CAVI) was developed as a new arterial stiffness index and is considered to be a surrogate marker of arteriosclerosis. The purpose of this study was to establish the role of LPL mass in arteriosclerosis by examining the relationship between LPL mass and CAVI in patients with arteriosclerotic risk factors. We studied 216 patients who attended our diabetic center with diagnoses of diabetes, hypertension and/or dyslipidemia. CAVI was measured using VaSera1500 (Fukuda Denshi, Tokyo). Serum level of LPL mass was measured by ELISA(Sekisui Co. Ltd.). When the subjects were divided by a CAVI cutoff level of 9.0, the glucose level, glycohemoglobin A1c (HbA1c) level and systolic blood pressure level were significantly higher in the over 9.0 individuals than in the under 9.0 individuals (p < 0.05). CAVI level was significantly higher in patients with hyperglycemia and hypertension. LPL mass was lower in subjects with higher CAVI than in those with lower CAVI. CAVI level correlated inversely with LPL mass. CAVI adjusted for the age was associated significantly with LPL mass. These results suggest that decreased LPL mass may be a risk marker for arteriosclerosis as indicated by the surrogate marker CAVI.

Association of Plasma Xanthine Oxidoreductase with Arterial Stiffness in Type 2 Diabetes with Liver Dysfunction.

BACKGROUND: Type 2 diabetes is a risk factor for atherosclerosis. Oxidative stress, which is a causative factor in insulin resistance, leads to atherosclerosis in patients with diabetes. Xanthine oxidoreductase (XOR) is an enzyme that catalyzes the oxidation of hypoxanthine to xanthine and xanthine to uric acid and is related to oxidative stress. We aimed to examine the influence of plasma XOR activity on arterial stiffness in patients with type 2 diabetes. METHODS: In total, 458 patients with type 2 diabetes not receiving antihyperuricemic agents were enrolled and their clinical parameters including plasma XOR activity and the cardio-ankle vascular index (CAVI) were measured. Patients were divided into the liver dysfunction and absence of liver dysfunction groups. Multiple regression analysis was performed. RESULTS: The median plasma XOR activity level was 64.3 pmol/h/mL (33.3-147.3 pmol/h/mL). Plasma XOR activity was correlated significantly and positively with aspartate transaminase and alanine transaminase (ρ > 0.5). The level of plasma XOR activity in the liver dysfunction group was eight-fold higher than that in the absence of liver dysfunction group. A significant positive correlation was observed between plasma XOR activity and the CAVI only in the liver dysfunction group (ρ = 0.3968, P < 0.0043). Multiple regression models demonstrated that plasma XOR activity was an independent predictor of the CAVI in the liver dysfunction group (P = 0.0055). CONCLUSIONS: Our results suggest that plasma XOR activity is associated with arterial stiffness and may have a role in atherosclerosis development in patients with type 2 diabetes and liver dysfunction.

Current Status of Familial LCAT Deficiency in Japan.

Lecithin cholesterol acyltransferase (LCAT) is a lipid-modification enzyme that catalyzes the transfer of the acyl chain from the second position of lecithin to the hydroxyl group of cholesterol (FC) on plasma lipoproteins to form cholesteryl acylester and lysolecithin. Familial LCAT deficiency is an intractable autosomal recessive disorder caused by inherited dysfunction of the LCAT enzyme. The disease appears in two different phenotypes depending on the position of the gene mutation: familial LCAT deficiency (FLD, OMIM 245900) that lacks esterification activity on both HDL and ApoB-containing lipoproteins, and fish-eye disease (FED, OMIM 136120) that lacks activity only on HDL. Impaired metabolism of cholesterol and phospholipids due to LCAT dysfunction results in abnormal concentrations, composition and morphology of plasma lipoproteins and further causes ectopic lipid accumulation and/or abnormal lipid composition in certain tissues/cells, and serious dysfunction and complications in certain organs. Marked reduction of plasma HDL-cholesterol (HDL-C) and corneal opacity are common clinical manifestations of FLD and FED. FLD is also accompanied by anemia, proteinuria and progressive renal failure that eventually requires hemodialysis. Replacement therapy with the LCAT enzyme should prevent progression of serious complications, particularly renal dysfunction and corneal opacity. A clinical research project aiming at gene/cell therapy is currently underway.

Laparoscopic Sleeve Gastrectomy Significantly Increases Serum Lipoprotein Lipase Level in Obese Patients.

OBJECTIVES: Obesity is one of the causes of metabolic disorders. Laparoscopic sleeve gastrectomy (LSG) confers beneficial effects not only on body weight (BW) but also on metabolic disorders. The lipoprotein lipase (LPL) level in preheparin serum is associated with visceral adipose tissue and reflects insulin resistance. However, the change in serum preheparin LPL levels after LSG remains unclear. This study aimed to examine the effect of LSG on preheparin LPL level in obese patients compared with nonsurgical treatment. METHODS: We retrospectively reviewed a total of 100 obese patients who were treated for obesity and had preheparin LPL levels measured before and 12 months after LSG or after 12 months of nonsurgical treatment. Fifty-six patients received LSG (LSG group), and 44 patients had no surgical treatment (nonsurgical group). We compared clinical parameters such as body mass index (BMI), hemoglobin A1c (HbA1c), and preheparin LPL level before and 12 months after treatment. RESULTS: BMI and HbA1c decreased significantly in both groups, but decreases in both parameters were greater in the LSG group than in the nonsurgical group. Estimated glomerular filtration was significantly improved only in the LSG group. Preheparin LPL level increased significantly only in the LSG group (from 45.8 ± 21.6 to 75.0 ± 34.9 ng/mL, p < 0.001). Multiple regression identified LSG and decreased BMI as independent predictors of preheparin LPL level increase. CONCLUSIONS: These results suggest that LSG independently increases pre-heparin LPL level beyond BW reduction in obese patients.

[Remnant lipoprotein cholesterol level measured by homogeneous assay reflects the quantity of intermediate-density lipoprotein].

Remnant lipoprotein can be measured by immunoseparation assay and polyacrylamide gel disc electrophoresis; however, these methods have some problems, such as a lack of specificity and being technically complicated. Recently, a new method, the remnant lipoprotein cholesterol homogeneous assay(RemL-C), has been established. In this study, we evaluated the basal performance of RemL-C assay. One hundred and fifty patients with diabetes mellitus were enrolled in this study. RemL-C level was higher in the midband (+) group than in the midband (-) group (p<0.01), and a strong correlation was observed between RemL-C level and remnant lipoprotein level measured by conventional method (r=0.89, p<0.01). RemL-C level correlated positively with triglyceride(TG) (r=0.94, p<0.01) and total cholesterol(TC) (r=0.39, p<0.01), negatively with high density lipoprotein(HDL-C) (r=-0.35, p<0.01) and positively with apolipoprotein (apo) CII, and apoE (apoCII: r=0.59, p<0.01, apoE: r=0.71, p<0.01). In particular, RemL-C level correlated strongly with TG and apoE. RemL-C level was significantly higher in patients with combined hyperlipidemia compared to patients with other hyperlipidemias (p<0.01). When the serum of a patient with combined hyperlipidemia was separated by sepharose 4B gel filtration, the fraction showing peak RemL-C level was observed between the fraction corresponding to VLDL and the fraction corresponding to LDL. Furthermore, the peak of RemL-C corresponded to the peak of apoE. Moreover RemL-C level correlated negatively with preheparin serum lipoprotein lipase mass that is a marker of metabolic syndrome (r=-0.30, p<0.01). These results suggest that the measurement of remnant lipoprotein by RemL-C assay reflects the quantity of intermediate-density lipoprotein. Since RemL-C measurement can be run on an automated clinical analyzer permitting quick and high throughput measurement, RemL-C levels may be useful in the screening of hyperlipidemia.

[Expression of toll-like receptor 4 in colorectal cancer].

Toll-like receptors (TLRs) play an essential role in innate immunity by recognizing various pathogens and by activating acquired immunity. Based on the hypothesis that abnormalities of innate immune responses are involved in carcinogenesis, we examined the presence or absence of the expression of Toll-like receptor 4 (TLR4), comprising one of the TLR families, in colorectal cancer tissues. TLR4 expression in cancerous and non-cancerous colorectal tissue specimens obtained at surgery was investigated by reverse-transcription polymerase chain reaction (RT-PCR). Then, TLR4 expression levels were quantified by real-time PCR and compared between the 2 groups. TLR4 expression was significantly higher in non-cancerous tissues than in cancerous tissues. Interestingly, these results suggested that TLR4 expression was up-regulated in non-cancerous tissues or down-regulated in cancerous tissues in patients with colorectal cancer.

Lp8 is potentially associated with partial lecithin:cholesterol acyltransferase deficiency in a patient with primary biliary cirrhosis.

BACKGROUND: The significance of Lp8, that is, abnormal lipoprotein(s) detected in fraction 8 by combined high-performance liquid chromatography/gel filtration column in patients with familial lecithin:cholesterol acyltransferase (LCAT) syndrome, in relation to the severity of LCAT deficiency has not been analyzed. OBJECTIVE: We have studied Lp8 in a patient with primary biliary cirrhosis. METHODS: Plasma lipoproteins were analyzed using high-performance liquid chromatography/gel filtration column in the course of treatment of a 47-year-old female patient with primary biliary cirrhosis. RESULTS: Electrophoretic lipoprotein analyses showed massive accumulation of abnormal ß- and preß-lipoproteins with a minor lipoprotein fraction at a position near the cathode corresponding to Lp-X, on day A (status: hypercholesterolemia, LCAT activity undetectable). Chromatographic lipoprotein subfraction analysis revealed free cholesterol- and phospholipid-rich lipoproteins in fractions 1-6, corresponding to chylomicrons and very low-density lipoprotein, and phospholipid- and triglyceride-rich lipoproteins with increased free cholesterol, that is, Lp8, in fractions 7-9 (corresponding to low-density lipoprotein). On day B, after additional treatment for 7 months (status: almost normolipidemia, decreased LCAT activity), although the abnormal lipoprotein and the lipoproteins in fractions 1-6, were drastically decreased, the presence of Lp8 persisted. CONCLUSIONS: Lp8 likely is a minor abnormal lipoprotein fraction in patients with mildly decreased secondary LCAT activity, as well as with severely reduced primary LCAT activity.

Vascular smooth muscle cell apoptosis induced by 7-ketocholesterol was mediated via Ca2+ and inhibited by the calcium channel blocker nifedipine.

Previous reports indicate that 7-ketocholesterol (7KCHO) induces apoptosis of cultured human vascular smooth muscle cells (SMCs). We hypothesized that calcium channel blockers will inhibit SMC apoptosis induced by 7KCHO because caspase-3 activity is Ca2+ dependent and 7KCHO stimulates caspase-3 and SMC apoptosis. So, the protective effect of the calcium channel blocker nifedipine on SMC apoptosis induced by 7KCHO was investigated. When 7KCHO (50 micromol/L) was added to SMCs, terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate (dUTP)-biotin nick end-labeling was positive. DNA extracted from SMCs exposed to 7KCHO showed a ladder pattern on agarose electrophoresis. In the presence of extracellular Ca2+, the Ca2+ influx, caspase-3 activity, and fragmented DNA also increased in SMCs incubated with 7KCHO dose-dependently. However, in the absence of extracellular Ca2+, no effects of 7KCHO on caspase-3 activity and fragmented DNA were observed. In the presence of nifedipine, the 7KCHO-induced increases in Ca2+ influx, caspase-3 activity, and the amount of fragmented DNA decreased significantly. These results suggest that 7KCHO-induced apoptosis of SMCs is inhibited by calcium channel blockade, and that Ca2+ influx into cells mediated by 7KCHO plays an important role in 7KCHO-induced apoptosis.

Preheparin serum lipoprotein lipase mass might be a biomarker of metabolic syndrome.

Lipoprotein lipase mass in preheparin serum (preheparin LPL mass) is assumed to reflect some of the LPL production in the whole body and insulin sensitivity. While metabolic syndrome is a common underlying condition for cardiovascular diseases, biological marker of this syndrome has not been fully established. To clarify the characteristics of preheparin LPL mass in metabolic syndrome, 362 Japanese subjects were studied to examine the relationship between symptoms of metabolic syndrome and preheparin LPL mass and compare with plasma adiponectin. Furthermore the relation with urinary 8-hydroxydeoxyguanosine (8-OHdG) that reflects oxidative stress to DNA was also studied. Both preheparin LPL mass and plasma adiponectin correlated positively with HDL-cholesterol and negatively with body weight and triglyceride. Only preheparin LPL mass showed a negative correlation with fasting blood glucose and HbA1c. Both mean preheparin LPL mass and plasma adiponectin decreased with an increase in severity of the metabolic syndrome with/without obesity and with/without diabetes. The correlation coefficient between preheparin LPL mass and plasma adiponectin was r=0.562. A negative correlation between preheparin LPL mass and urinary 8-OHdG was observed. These results suggest that low preheparin LPL mass may reflect systemic oxidative stress and also a biomarker of the severity of metabolic syndrome.

Effect of metformin on serum lipoprotein lipase mass levels and LDL particle size in type 2 diabetes mellitus patients.

We previously reported that lipoprotein lipase mass levels in preheparin serum (preheparin LPL mass) was significantly lower in type 2 diabetes mellitus compared to healthy subjects and that low preheparin LPL mass may be a high-risk factor of coronary atherosclerosis. The aim of this study was to clarify the effects of metformin on serum lipoprotein lipase mass levels (preheparin LPL mass), adiponectin and lipid metabolism in patients with type 2 diabetes mellitus. Twenty-eight patients with type 2 diabetes mellitus (HbAlc>7.0%), who were already receiving sulfonylurea agents, took metformin 500 mg orally twice daily for 3 months. Fasting blood glucose (FBG), immunoreactive insulin (basal IRI) and HbAlc decreased significantly after metformin treatment. LDL-Rm ratio decreased significantly (from 0.3521+/-0.046 to 0.3339+/-0.030, P<0.05) and preheparin LPL mass increased significantly (from 42.5+/-3.2 to 50.6+/-3.5 ng/ml, P<0.0005), but adiponectin was unchanged. The correlation of a change of LDL-Rm ratio and a change of preheparin LPL mass showed a negative correlation tendency. The changes in LDL-Rm ratio and preheparin LPL mass were independent of the hypoglycemic effect of metformin. These results suggest that metformin may increase LPL production, thereby increasing LDL particle size. These effects might be independent of the hypoglycemic effect of metformin.

Severely impaired activity of lipoprotein lipase Arg243His is partially ameliorated by emulsifying phospholipids in in vitro triolein hydrolysis analysis.

Background We investigated the in vitro effects of various phospholipids as emulsifiers on the hydrolysing activities of lipoprotein lipase (LPL) Arg243His against triolein as substrate. LPL Arg243His, identified in a patient with hyperchylomicronaemia, displays severely diminished activity for triolein when emulsified with Triton X-100. Methods Lipolytic activities of plasma obtained by heparin injection from a homozygous patient with LPL Arg243His were analysed using triolein emulsified with phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylserine (PS), phosphatidylinositol (PI), lysophosphatidylcholine (LPC), or Triton X-100 as substrates. Results The hydrolysing activities of the patient's plasma for triolein emulsified with PC, PE, PS, PI, LPC and Triton X-100 were 9.22 ± 1.06 µmol/ml/h/ngLPL, 2.94 ± 1.60 µmol/ml/h/ng LPL, 3.72 ± 1.63 µmol/ml/h/ng LPL, 3.40 ± 1.20 µmol/ml/h/ngLPL, 3.72 ± 1.96 µmol/ml/h/ngLPL and 7.80 ± 4.48 µmol/ml/h/ng LPL, respectively. Thus, the specific activities of the patient's LPL determined with triolein emulsified with PC were significantly higher than those with PE, PS, PI or LPC as emulsifiers. Relative to the activities of normal plasma measured with PC, PE, PS, PI and LPC as emulsifiers, the mutant's activities were 49.1 ± 5.2%, 44.1 ± 5.7%, 31.7 ± 12.6%, 19.2 ± 6.9% and 23.8 ± 11.3%, respectively. Using PC, PE, PS, PI and LPC as emulsifiers, the mutant's activities for triolein-lipolysis relative to normal were significantly increased in comparison to the relative activity measured with the classical emulsifier, Triton X-100 (12.9 ± 6.7%). Conclusions Impaired triolein hydrolysis by LPL Arg243His was partially ameliorated by triolein emulsification with phospholipids. The in vitro analysis of triolein hydrolysis using various phospholipid emulsifiers may be useful for the further understanding of impaired LPL function.

The angiotensin II receptor antagonist valsartan enhances lipoprotein lipase mass in preheparin serum in type 2 diabetes with hypertension.

Recent studies suggest that blockade of angiotensin type 1 (AT1) receptor may have some effect on glucose and lipoprotein metabolism. Serum level of preheparin lipoprotein lipase (LPL) reflects LPL production mainly in adipocytes and is believed to be related to insulin sensitivity. We studied the effect of a selective AT1 antagonist, valsartan, on glucose, lipid metabolism and the preheparin LPL mass in 55 patients with type 2 diabetes and hypertension. Patients were randomized into a group administered valsartan 80 mg/day for 12 weeks or a group not administered valsartan (control). Blood pressure decreased significantly. HbA1c and TG levels decreased and HDL-C level increased, but these changes tended to be significantly different. TC and LDL-C levels were not significant changes. Preheparin LPL mass increased after valsartan administration compared with control (P = 0.0307), and migration ratio of LDL (LDL-Rm), which correlated negatively with LDL particle size, decreased compared with control (P < 0.0001). DeltaLDL-Rm correlated inversely with Delta preheparin LPL mass (r = -0.459). Among subjects treated with valsartan, greater improvement in preheparin LPL mass and blood pressure was observed in the subgroup with preheparin LPL mass <40 ng/ml. The results of this study suggest that valsartan may enhance LPL production in adipocytes, resulting in enlarged LDL particle size.