Extracellular Vimentin Alters Energy Metabolism And Induces Adipocyte Hypertrophy.

BACKGRUOUND: Previous studies have reported that oxidative stress contributes to obesity characterized by adipocyte hypertrophy. However, mechanism has not been studied extensively. In the current study, we evaluated role of extracellular vimentin secreted by oxidized low-density lipoprotein (oxLDL) in energy metabolism in adipocytes. METHODS: We treated 3T3-L1-derived adipocytes with oxLDL and measured vimentin which was secreted in the media. We evaluated changes in uptake of glucose and free fatty acid, expression of molecules functioning in energy metabolism, synthesis of adenosine triphosphate (ATP) and lactate, markers for endoplasmic reticulum (ER) stress and autophagy in adipocytes treated with recombinant vimentin. RESULTS: Adipocytes secreted vimentin in response to oxLDL. Microscopic evaluation revealed that vimentin treatment induced increase in adipocyte size and increase in sizes of intracellular lipid droplets with increased intracellular triglyceride. Adipocytes treated with vimentin showed increased uptake of glucose and free fatty acid with increased expression of plasma membrane glucose transporter type 1 (GLUT1), GLUT4, and CD36. Vimentin treatment increased transcription of GLUT1 and hypoxia-inducible factor 1α (Hif-1α) but decreased GLUT4 transcription. Adipose triglyceride lipase (ATGL), peroxisome proliferator-activated receptor γ (PPARγ), sterol regulatory element-binding protein 1 (SREBP1), diacylglycerol O-acyltransferase 1 (DGAT1) and 2 were decreased by vimentin treatment. Markers for ER stress were increased and autophagy was impaired in vimentin-treated adipocytes. No change was observed in synthesis of ATP and lactate in the adipocytes treated with vimentin. CONCLUSION: We concluded that extracellular vimentin regulates expression of molecules in energy metabolism and promotes adipocyte hypertrophy. Our results show that vimentin functions in the interplay between oxidative stress and metabolism, suggesting a mechanism by which adipocyte hypertrophy is induced in oxidative stress.

ANGPTL3 Deficiency and Risk of Hepatic Steatosis.

BACKGROUND: ANGPTL3 (angiopoietin-like 3) is a therapeutic target for reducing plasma levels of triglycerides and low-density lipoprotein cholesterol. A recent trial with vupanorsen, an antisense oligonucleotide targeting hepatic production of ANGPTL3, reported a dose-dependent increase in hepatic fat. It is unclear whether this adverse effect is due to an on-target effect of inhibiting hepatic ANGPTL3. METHODS: We recruited participants with ANGPTL3 deficiency related to ANGPTL3 loss-of-function (LoF) mutations, along with wild-type (WT) participants from 2 previously characterized cohorts located in Campodimele, Italy, and St. Louis, MO. Magnetic resonance spectroscopy and magnetic resonance proton density fat fraction were performed to measure hepatic fat fraction and the distribution of extrahepatic fat. To estimate the causal relationship between ANGPTL3 and hepatic fat, we generated a genetic instrument of plasma ANGPTL3 levels as a surrogate for hepatic protein synthesis and performed Mendelian randomization analyses with hepatic fat in the UK Biobank study. RESULTS: We recruited participants with complete (n=6) or partial (n=32) ANGPTL3 deficiency related to ANGPTL3 LoF mutations, as well as WT participants (n=92) without LoF mutations. Participants with ANGPTL3 deficiency exhibited significantly lower total cholesterol (complete deficiency, 78.5 mg/dL; partial deficiency, 172 mg/dL; WT, 188 mg/dL; P<0.05 for both deficiency groups compared with WT), along with plasma triglycerides (complete deficiency, 26 mg/dL; partial deficiency, 79 mg/dL; WT, 88 mg/dL; P<0.05 for both deficiency groups compared with WT) without any significant difference in hepatic fat (complete deficiency, 9.8%; partial deficiency, 10.1%; WT, 9.9%; P>0.05 for both deficiency groups compared with WT) or severity of hepatic steatosis as assessed by magnetic resonance imaging. In addition, ANGPTL3 deficiency did not alter the distribution of extrahepatic fat. Results from Mendelian randomization analyses in 36 703 participants from the UK Biobank demonstrated that genetically determined ANGPTL3 plasma protein levels were causally associated with low-density lipoprotein cholesterol (P=1.7×10-17) and triglycerides (P=3.2×10-18) but not with hepatic fat (P=0.22). CONCLUSIONS: ANGPTL3 deficiency related to LoF mutations in ANGPTL3, as well as genetically determined reduction of plasma ANGPTL3 levels, is not associated with hepatic steatosis. Therapeutic approaches to inhibit ANGPTL3 production in hepatocytes are not necessarily expected to result in the increased risk for hepatic steatosis that was observed with vupanorsen.

Fatty acids as a direct regulator of aldosterone hypersecretion.

Primary hyperaldosteronism is a major cause of secondary hypertension and carries additional cardiovascular risks beyond that of the elevated blood pressure. Primary hyperaldosteronism is more prevalent in obese people, and weight loss reduces aldosterone levels. It needs to be determined whether obesity related factors directly contribute to the pathogenesis of primary hyperaldosteronism. Here we show that the non-esterified fatty acids (NEFA) palmitic acid, and to a lesser extent, linoleic acid significantly stimulated aldosterone production and steroid enzyme induction in adrenocortical HAC15 cells of human origin. Palmitic acid, linoleic acid, and to a much lesser extent, oleic acid induced the expression of aldosterone synthase. Induction of the Steroidogenic Acute Regulatory Protein (StAR) was modest. Increased aldosterone secretion was independent of fatty acid beta-oxidation in the mitochondria but may involve free fatty acid receptor 1 (FFAR1/GPR40) and endoplasmic reticulum (ER) stress. Palmitic acid and linoleic acid induced the expression of C/EBP Homologous Protein (CHOP), a marker of ER stress, correlating with their ability to induce aldosterone synthase gene expression. Palmitic acid, but not linoleic acid decreased mitochondrial potentials and induced uncoupling protein 2 (UCP2). Palmitic acid enhanced, while docosahexaenoic acid (DHA) suppressed aldosterone response to angiotensin II (Ang-II). Our study provides evidence that NEFAs modulate aldosterone production, and further suggests that hyperaldosteronism shares similar pathogenesis with other obesity-related disorders such as metabolic syndrome.

[Effect and mechanism of cardiac adipose triglyceride lipase overexpression on burn-induced cardiac injury].

Objective: To explore the effect and potential mechanism of cardiac adipose triglyceride lipase (ATGL) overexpression on burn-induced cardiac injury. Methods: Eight-week-old C57BL/6J mice with cardiac ATGL overexpression driven by the myosin heavy chain (MHC) promoter (MHC-ATGL burn group) and wild-type (wild-type burn group) mice were randomly chose to the following experiments with burn injury after 24 h (n=8/group), MHC-ATGL mice and wild-type mice with corresponded age and sex were included as control. Cardiac ATGL protein expression, serum levels of cardiac troponin T and cardiac kinase-MB (CK-MB), cardiac free fatty acid and reactive oxygen species were detected. The wild-type and MHC-ATGL burn groups were not only compared with their corresponded control groups, but also compared between each other. Results: The hair color and development were shown little difference between each group. ATGL protein expression is elevated in wild-type burn group (1.00±0.68 vs 3.09±0.93, P=0.023) and decreased in MHC-ATGL burn group (17.84±2.41 vs 10.36±2.22, P<0.001), while ATGL protein expression is still increased in MHC-ATGL burn group compared with wild-type burn group (P<0.001). Serum levels of cardiac troponin T and CK-MB were both elevated in wild-type burn group and MHC-ATGL burn group [(0.456±0.131) vs (0.076±0.019) µg/L and (0.219±0.089) vs (0.060±0.019) µg/L, (1 421±162) vs (221±67) U/L and (761±142) vs (221±41) U/L] (all P<0.001), while serum levels of cardiac troponin T and CK-MB was still decreased in MHC-ATGL burn group compared with wild-type burn group (P<0.001). In addition, cardiac free fatty acid was increased in wild-type burn group and little difference was found in MHC-ATGL burn group [(2.54±0.51) vs (0.46±0.27) mmol/L, P<0.001, and (0.81±0.38) vs (0.59±0.25) mmol/L, P=0.251], while cardiac free fatty acid was significant reduction in MHC-ATGL burn group compared with wild-type burn group (P<0.001). Levels of cardiac reactive oxygen species was both elevated in wild-type burn group and MHC-ATGL burn group [(1.89±0.23) vs (1.00±0.18) and (1.38±0.17) vs (0.95±0.13)] (both P<0.001), while levels of cardiac reactive oxygen was reduction in MHC-ATGL burn group compared with wild-type burn group (P<0.001). Conclusion: Cardiac ATGL overexpression may protect against burn-induced cardiac injury through reducing free fatty acid and reactive oxygen species production.

Comparison of the Efficacy of Rosuvastatin Monotherapy 20 mg with Rosuvastatin 5 mg and Ezetimibe 10 mg Combination Therapy on Lipid Parameters in Patients with Type 2 Diabetes Mellitus.

BACKGROUND: The apolipoprotein B/A1 (apoB/A1) ratio is a stronger predictor of future cardiovascular disease than is the level of conventional lipids. Statin and ezetimibe combination therapy have shown additional cardioprotective effects over statin monotherapy. METHODS: This was a single-center, randomized, open-label, active-controlled study in Korea. A total of 36 patients with type 2 diabetes mellitus were randomized to either rosuvastatin monotherapy (20 mg/day, n=20) or rosuvastatin/ezetimibe (5 mg/10 mg/day, n=16) combination therapy for 6 weeks. RESULTS: After the 6-week treatment, low density lipoprotein cholesterol (LDL-C) and apoB reduction were comparable between the two groups (-94.3±15.4 and -62.0±20.9 mg/dL in the rosuvastatin group, -89.9±22.7 and -66.8±21.6 mg/dL in the rosuvastatin/ezetimibe group, P=0.54 and P=0.86, respectively). In addition, change in apoB/A1 ratio (-0.44±0.16 in the rosuvastatin group and -0.47±0.25 in the rosuvastatin/ezetimibe group, P=0.58) did not differ between the two groups. On the other hand, triglyceride and free fatty acid (FFA) reductions were greater in the rosuvastatin/ezetimibe group than in the rosuvastatin group (-10.5 mg/dL [interquartile range (IQR), -37.5 to 29.5] and 0.0 µEq/L [IQR, -136.8 to 146.0] in the rosuvastatin group, -49.5 mg/dL [IQR, -108.5 to -27.5] and -170.5 µEq/L [IQR, -353.0 to 0.8] in the rosuvastatin/ezetimibe group, P=0.010 and P=0.049, respectively). Both treatments were generally well tolerated, and there were no differences in muscle or liver enzyme elevation. CONCLUSION: A 6-week combination therapy of low-dose rosuvastatin and ezetimibe showed LDL-C, apoB, and apoB/A1 ratio reduction comparable to that of high-dose rosuvastatin monotherapy in patients with type 2 diabetes mellitus. Triglyceride and FFA reductions were greater with the combination therapy than with rosuvastatin monotherapy.

Comparison of the Efficacy of Rosuvastatin Monotherapy 20 mg with Rosuvastatin 5 mg and Ezetimibe 10 mg Combination Therapy on Lipid Parameters in Patients with Type 2 Diabetes Mellitus

BACKGROUND: The apolipoprotein B/A1 (apoB/A1) ratio is a stronger predictor of future cardiovascular disease than is the level of conventional lipids. Statin and ezetimibe combination therapy have shown additional cardioprotective effects over statin monotherapy. METHODS: This was a single-center, randomized, open-label, active-controlled study in Korea. A total of 36 patients with type 2 diabetes mellitus were randomized to either rosuvastatin monotherapy (20 mg/day, n=20) or rosuvastatin/ezetimibe (5 mg/10 mg/day, n=16) combination therapy for 6 weeks. RESULTS: After the 6-week treatment, low density lipoprotein cholesterol (LDL-C) and apoB reduction were comparable between the two groups (−94.3±15.4 and −62.0±20.9 mg/dL in the rosuvastatin group, −89.9±22.7 and −66.8±21.6 mg/dL in the rosuvastatin/ezetimibe group, P=0.54 and P=0.86, respectively). In addition, change in apoB/A1 ratio (−0.44±0.16 in the rosuvastatin group and −0.47±0.25 in the rosuvastatin/ezetimibe group, P=0.58) did not differ between the two groups. On the other hand, triglyceride and free fatty acid (FFA) reductions were greater in the rosuvastatin/ezetimibe group than in the rosuvastatin group (−10.5 mg/dL [interquartile range (IQR), −37.5 to 29.5] and 0.0 µEq/L [IQR, −136.8 to 146.0] in the rosuvastatin group, −49.5 mg/dL [IQR, −108.5 to −27.5] and −170.5 µEq/L [IQR, −353.0 to 0.8] in the rosuvastatin/ezetimibe group, P=0.010 and P=0.049, respectively). Both treatments were generally well tolerated, and there were no differences in muscle or liver enzyme elevation. CONCLUSION: A 6-week combination therapy of low-dose rosuvastatin and ezetimibe showed LDL-C, apoB, and apoB/A1 ratio reduction comparable to that of high-dose rosuvastatin monotherapy in patients with type 2 diabetes mellitus. Triglyceride and FFA reductions were greater with the combination therapy than with rosuvastatin monotherapy.

Effect of ghrelin O-acyltransferase inhibition by small interfering RNA on hepatocyte fatty degeneration and related mechanism of action / 临床肝胆病杂志

Objective To investigate the effect of inhibition of ghrelin O-acyltransferase (GOAT) by small interfering RNA (siRNA) on hepatocyte fatty degeneration and related mechanism of action.Methods Human LO2 hepatocytes were treated with free fatty acid (FFA)to induce hepatocyte fatty degeneration.LO2 hepatocytes were treated with FFA and siRNA-GOAT alone or in combination and then divided into normal control (NC) group (treated with phosphate buffered saline alone),siRNA-GOAT group (treated with siRNA-GOAT at a final concentration of 10 nm),FFA group (treated with FFA at a final concentration of 1 mm),and FFA + siRNA-GOAT group (treated with FFA at a final concentration of 1 mm and siRNA-GOAT at a final concentration of 10 nm).Oil red O staining was performed for hepatocytes to identify lipid droplets;the triglyceride (TG) test kit was used to measure the lipid level in LO2 hepatocytes;Western blot,qRT-PCR,immunofluorescent staining,and electron microscopy were used to measure autophagy;ELISA and RT-PCR were used to measure the levels of tumor necrosis factor-α (TNFα) and interleukin-6 (IL-6);ELISA was used to measure the changes in the levels of mammalian target of rapamycin (mTOR),phosphorylated mTOR (p-mTOR),AMP-activated protein kinase (AMPK),and phosphorylated AMPK.A one-way analysis of variance was used for comparison between multiple groups,and the least significant difference t-test was used for further comparison between any two groups.Results Compared with the FFA group,the FFA + siRNA-GOAT group had a significant reduction in the formation of lipid droplets and a significantly lower TG level (P ＜0.001).Compared with the FFA group,the FFA + siRNA-GOAT group had significant reductions in the protein and mRNA expression of TNFα and IL-6 (all P ＜ 0.005).The siRNA + GOAT group had significantly higher mRNA expression of LC3-Ⅱ and Beclin-1 than the NC group (all P ＜0.001).The FFA + siRNA-GOAT group had significantly higher mRNA expression of LC3-Ⅱ and Beclin-1 than the FFA group (all P ＜0.001).The siRNA + GOAT group had significantly higher protein expression of LC3-Ⅱ and Beclin-1 than the NC group (all P ＜ 0.05).The FFA + siRNA-GOAT group had significantly higher protein expression of LC3-Ⅱ and Beclin-1 than the FFA group (all P ＜ 0.05).Immunofluorescent staining showed that compared with the FFA group and the siRNA-GOAT group,the FFA + siRNA-GOAT group had a significant increase in the expression of endogenous LC3-Ⅱ in LO2 hepatocytes.Electron microscopy showed that compared with the FFA group,the FFA + siRNA-GOAT group had a significant increase in the expression of autophagosome.After the LO2 hepatocytes were treated by autophagy inhibitors siRNA-ATG5 and 3-MA or an autophagy stimulant,rapamycin,there was a significant difference in TG level between the FFA + siRNA-ATG5 group and the FFA + siRNA-GOAT group (P ＜ 0.001),as well as between the FFA + 3-MA group and the FFA + rapamycin group (P ＜ 0.001).The FFA + siRNA-GOAT group had a significantly higher level of LC3-Ⅰ/Ⅱ than the FFA + siRNA-ATG5 group (P ＜0.05),and the FFA + rapamycin group had a significantly higher level of LC3-Ⅰ/Ⅱ than the FFA + 3-MA group (P ＜ 0.05).Compared with the FFA group,the FFA + siRNA-GOAT group had significantly higher protein expression of p-AMPK (P ＜ 0.05) and significantly lower protein expression of p-rmTOR (P ＜ 0.05).Conclusion GOAT inhibition by siRNA can upregnlate autophagy and alleviate hepatocyte fatty degeneration,possibly by regulating the AMPK/mTOR pathway.

In Vitro Effect of Fatty Acids Identified in the Plasma of Obese Adolescents on the Function of Pancreatic ß-Cells.

BACKGROUND: The increase in circulating free fatty acid (FFA) levels is a major factor that induces malfunction in pancreatic ß-cells. We evaluated the effect of FFAs reconstituted according to the profile of circulating fatty acids found in obese adolescents on the viability and function of the murine insulinoma cell line (mouse insulinoma [MIN6]). METHODS: From fatty acids obtained commercially, plasma-FFA profiles of three different youth populations were reconstituted: obese with metabolic syndrome; obese without metabolic syndrome; and normal weight without metabolic syndrome. MIN6 cells were treated for 24 or 48 hours with the three FFA profiles, and glucose-stimulated insulin secretion, cell viability, mitochondrial function and antioxidant activity were evaluated. RESULTS: The high FFA content and high polyunsaturated ω6/ω3 ratio, present in plasma of obese adolescents with metabolic syndrome had a toxic effect on MIN6 cell viability and function, increasing oxidative stress and decreasing glucose-dependent insulin secretion. CONCLUSION: These results could help to guide nutritional management of obese young individuals, encouraging the increase of ω-3-rich food consumption in order to reduce the likelihood of deterioration of ß-cells and the possible development of type 2 diabetes mellitus.

In Vitro Effect of Fatty Acids Identified in the Plasma of Obese Adolescents on the Function of Pancreatic β-Cells

BACKGROUND: The increase in circulating free fatty acid (FFA) levels is a major factor that induces malfunction in pancreatic β-cells. We evaluated the effect of FFAs reconstituted according to the profile of circulating fatty acids found in obese adolescents on the viability and function of the murine insulinoma cell line (mouse insulinoma [MIN6]). METHODS: From fatty acids obtained commercially, plasma-FFA profiles of three different youth populations were reconstituted: obese with metabolic syndrome; obese without metabolic syndrome; and normal weight without metabolic syndrome. MIN6 cells were treated for 24 or 48 hours with the three FFA profiles, and glucose-stimulated insulin secretion, cell viability, mitochondrial function and antioxidant activity were evaluated. RESULTS: The high FFA content and high polyunsaturated ω6/ω3 ratio, present in plasma of obese adolescents with metabolic syndrome had a toxic effect on MIN6 cell viability and function, increasing oxidative stress and decreasing glucose-dependent insulin secretion. CONCLUSION: These results could help to guide nutritional management of obese young individuals, encouraging the increase of ω-3-rich food consumption in order to reduce the likelihood of deterioration of β-cells and the possible development of type 2 diabetes mellitus.

The influence of cholecystokinin-octopeptide on oxidative stess in islet beta cells injured by free fat acids / 重庆医学

Objective To observe the effect of cholecystokinin-octopeptide(CCK-8) on oxidative stress and cell proliferation in mice islet β cells (NIT-1 cells) injured by high concentration free fat acids .Methods In vitro cultured NIT-1 cells were divided into 3 groups ,they were control group ,FFAs group (add 0 .25 mmol/mL of oleinic acid + 0 .25 mmol/mL of palmic acid) and CCK-8 group (add FFAs and 1 × 10 - 8 mmol/L of CCK-8 simultaneously) .Cell morphologies were observed ;NIT-1 cells proliferations were detected by M TT method ,and apoptosis rates were measured by flow cytometry ;The levels of T-AOC ,GSH-Px ,CAT ,SOD and MDA in supernatant were also measured .Results There were less cell debris in CCK-8 group than FFAs group(all P< 0 .01) ;the OD570 value of CCK-8 group was significant higher than FFAs group(P< 0 .01) ,and the 72 h CCK-8 group was higher than 48 h CCK-8 group(P< 0 .01) .Compared with FFAs group ,the levels of CAT ,T-AOC ,SOD and GSH-Px in CCK-8 group were in-creased and the concentration of MDA was decreased obviously(P< 0 .05) ,the levels of CAT ,SOD in 72 h CCK-8 group were high-er than 48 h CCK-8 group ,MDA was lower than 48 h CCK-8 group(P< 0 .05) .Conclusion CCK-8 could protect islet β cells injury from FFAs through anti-oxidative stress mechanism and promote NIT-1 cells proliferation .

The levels and clinical value of serum free fatty acid in patients with ankylosin g spondylitis / 中华风湿病学杂志

Objective To study the association between serum free fatty acid (FFA) and ankylosing spondylitis (AS).Methods According to the classification criteria,a total of 90 newly diagnosed AS patients,223 healthy individuals and 82 patients with non-inflammatory diseases were divided into three groups,and biochemistry and immunology biomarks were measured in all individuals.One-Way analysis of variance (ANOVA) test was used to compare the difference between the three groups in the serum indexes,and Logistic regression analysis was used to identify AS risk factors associated with AS.Results There were no significant differences in gender,age,body mass index (BMI),white blood cells (WBC),high-level data link control (HDL-C),low-density lipoprotein control (LDL-C),lipoproteins [Lp (a)],alkaline phosphatase (ALP) and TG in the three groups,and our results showed that serum FFA was statistical different between the three groups (F=24.191,P＜0.01),the serum level of FFA in patients with AS was higher compared with patients with noninflammatory diseases and healthy controls [(0.48 ±0.18) mmol/L,(0.28 ±0.09) mmol/L,(0.29±0.16) mmol/L;t=-5.969,P＜0.01;t=5.106,P＜0.01].Seral IgA,IgG,IgM levels,ESR and CRP were statistically different between the three groups (F=14.870,P＜0.01;F=16.464,P＜0.01;F=4.124,P=0.018;F=97.002,P＜0.01;F=22.069,P＜0.01).Gender,age,BMI,serum IgA,IgM,ALP,HDL-C,LDL-C,Lp(a) and TG levels were not associated with AS by logistic regression analysis.However,serum IgG level,ESR and CRP were associated with AS [OR05％CI):1.659(1.032,2.660),P=0.037;OR05％CI):1.340(1.005,1.787),P=0.046;OR05％CI):1.820 (1.025,3.232),P=0.041],and there is an association between FFA and AS was observed in logistic regression analysis (OR=1.132,95％CI:1.014-1.421,P=0.033).Conclusion We suggest that incre-ased FFA is closely associated with AS,and may be an underlying risk factor for AS.

The effect of therapeutic life style on serum FFA and constitution index in patients with coronary heart disease complicated metabolic syndrome / 重庆医学

Objective To investigate the level of serum free fatty acid (FFA )after improving the life style in patients with coronary heart disease complicated metabolic syndrome and the effect of therapeutic life style on traditional risk factors of coronary artery disease.Methods A total of 395 patients with coronary heart disease complicated metabolic syndrome were recruited.Pa-tients were divided into intervention group (group A,conventional drug therapy+ intensive life style intervention,n=97)and non-intervention group (group B,conventional drug therapy,n=38)according to the scores of life style.Serum free fatty acid (FFA) was determined by ELASA.The scores of life style was obtained bylife style questionnaire.Results (1)The serum FFA of pa-tients with coronary heart disease complicated metabolic syndrome were positively related to waist circumference and waist-high-ra-tio.(2)Waist circumference,BMI and FFA of group A were significantly lower than those in group B after therapeutic life style in-tervention(P <0.05).(3)Compared with the baseline,the constitution index and FFA in group A were significantly lower after 6-months therapeutic life style intervention(P <0.05).Conclusion Therapeutic life style can reduce the level of FFA and constitution index of the patients with coronary heart disease complicated metabolic syndrome.

The changes of LCHAD in preeclampsia with different clinical features and the correlation with NADPH P47-phox, p38MAPK- α, COX-2 and serum FFA and TG / 中华妇产科杂志

Objective To investigate the changes of fatty acid oxidase in the placenta of preeclampsia cases with different clinical features, and the relationship with oxidative stress and inflammatory response. To study the correlation of serum free fatty acid (FFA) and triglycerides (TG) level in early second trimester with the molecular changes of the long-chain fatty acid oxidase in the third trimester. Methods This was prospective cohort study, in which cases with singleton pregnancies who archived in Haidian Maternal and Children′s Hospital, Beijing, from January 1st 2012 to May 31st, with regular prenatal care were included. Doppler ultrasound was used for screening for the presence of early diastolic notch of uterine artery at 22-24 weeks of gestation. All the 101 cases with the early diastolic notch of uterine artery were included as the notch group, and 377 cases without the early diastolic notch of uterine artery were included as the non-notch group. The perinatal outcomes and the incidence of hypertensive disorders in pregnancy of the two groups were observed. The serum level of FFA and TG was tested, and the mRNA and protein expression of long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD), P47-phox subunit of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, p38 mitogen-activated protein kinase α (p38MAPK-α) and cyclooxygenase-2 (COX-2) were detected using real-time quantitative PCR and western blot. The relationship between serum level of FFA and TG and the mRNA and protein expression of LCHAD, NADPH P47-phox,p38MAPK-α and COX-2 of the placental tissue specimens were analyzed. Results (1) In the notch group, there were 9 cases of early-onset preeclampsia,15 cases of late-onset preeclampsia and 10 cases of gestational hypertension;and there were 8 cases of late-onset preeclampsia and 18 cases of gestational hypertension in the non-notch group. 15 cases with normal blood pressure in each group were randomly selected as the control group.(2)The serum level of TG of cases of early-onset preeclampsia, late-onset preeclampsia and gestational hypertension in the notch group were(2.0±0.8),(1.8±0.6)and (1.9±0.7)mmol/L, and that of FFA were(0.68±0.26),(0.52±0.10)and(0.52±0.17)mmol/L, respectively. The serum level of TG of cases of late-onset preeclampsia and gestational hypertension in the non-notch group were(1.6±0.6)and(1.4±0.4)mmol/L, and that of FFA were(0.49±0.11)and(0.48±0.05)mmol/L, respectively. The serum level of TG and FFA in the control group were(1.4±0.5)and(0.52±0.06)mmol/L, respectively. The TG level of the notch group was higher than that of the control group, and the difference was statistically significant (P 0.05).(6)The mRNA expression of placental LCHAD in the early-onset preeclampsia in the notch group was significantly negatively correlated with the mRNA expression of placental NADPH P47-phox and COX-2 (r=- 0.877,-0.762, P<0.05). The mRNA expression of placental LCHAD in the control group was significantly negatively correlated with the mRNA expression of placental COX-2 (r=- 0.565, P<0.01). The protein expression of placental LCHAD in the early-onset preeclampsia in the notch group was significantly negatively correlated with the protein expression of NADPH P47-phox (r=- 0.818, P<0.01). The protein expression of placental LCHAD in the control group was significantly negatively correlated with the protein expression of COX-2 (r=- 0.502,P<0.01). Conclusions The placental mRNA and protein expression of long-chain fatty acid oxidation enzymes were different in different clinical features of preeclampsia, which were reduced more obviously in the early-onset preeclampsia in the notch group than that of the late-onset preeclampsia in the notch group, and were negatively correlated with the elevated serum FFA level, significantly enhanced oxidative stress and inflammatory response, but with no correlation with serum TG level.

Plasma free fatty acids composition and its association with nonalcoholic fatty liver disease / 重庆医学

Objective To study the relationship between plasma free fatty acids composition and the incidence of nonalcoholic fatty liver disease(NAFLD) .Methods By the design of case‐control study ,105 patients with NAFLD as cases and 110 healthy peo‐ple as controls were enrolled into the study .Plasma free fatty acid levels were determined by gas chromatography .Results High level of plasma palmitic acid(C16 :0)(OR=1 .769) was the risk factors of NAFLD ,while plasma levels of linoleic acid(C18 :2 n‐6) (OR=0 .855) and arachidonic acid(C20 :4 n‐6)(OR=0 .181)were negatively associated with the incidence of NAFLD .Conclusion These findings suggest that a proper ratio of diet fatty acids intake may reduce the risk of NAFLD .

Establishment and Application of Hyperinsulinemic-Euglycemic Clamp Technique in Conscious Rats / 天津医药

Objective To establish the hyperinsulinemic-euglycemic clamp(HEC) technique in conscious rats, and to explore the effect of acute infusion of lipid on glucose infusion rate (GIR) in rats. Methods Ten SD rats were random-ly divided into two groups, 5 rats for each group. The right jugular vein and left carotid artery were catheterized and under-went a HEC with infusion of lipid (intralipid group) for 6 hours, and with continuing infusion of 5%glucose (control group). The plasma levels of free fatty acid(FFA) and GIR were measured by HEC method. Results The level of FFA concentration increased by 17.6-fold, and GIR was reduced by 27%in the intralipid group compared to those of control group (P＜0.001). Conclusion The rat model of HEC has been successfully established by intravenous intralipid infusion, which can be con-firmed by HEC technique.

The Correlation Analysis of CHGA and ATGL in Patients of Type 2 Diabetes Mellitus with Nonalcoholic Fatty Liver Disease / 天津医药

Objective To investigate the relationship between plasma levels of chromogranin A (CHGA) and adi-pose triglyceride lipase (ATGL) in patients with type 2 diabetes (T2DM) combined non-alcoholic fatty liver disease (NAFLD). Methods The plasma levels of CHGA and ATGL were assayed by enzyme-linked immunosorbent assay (ELISA) in T2DM patients with NAFLD (group A, n=74), T2DM without NAFLD (group B, n=76), and normal group (group NC, n=75). The correlation between CHGA, ATGL and other metabolic index was analyzed. Results The plasma level of CHGA was significantly higher in group A (83.15±9.46) and group B (70.90±2.75) than that of group NC (46.74±8.15, P<0.01), and the level of CHGA was significantly higher in group A than that of group B (P<0.01). The plasma level of ATGL was sig-nificantly lower in group A (21.36±13.42) and group B (40.29±22.83) than that of group NC (72.30±26.41, P<0.01), and the level was lower in group A than that of group B (P<0.01). There was a negative correlation between the plasma CHGA, AT-GL and carbohydrate oxidation rate in group A. There was a positive correlation between fasting insulin (FINS), insulin resis-tance index (HOMA-IR), free fatty acid (FFA) and fat oxidation rate in group A. There was a negative correlation between plasma level ATGL and body mass index (BMI), FINS, cholesterol (TC), triglyceride (TG) and HOMA-IR, meanwhile, it was positively correlated with FFA. The multiple stepwise regression analysis showed that FINS, ATGL and FFA were indepen-dent variables for CHGA. The Logistic regression analysis showed that plasma levels of CHGA, ATGL and FFA were the in-dependent predictors of T2DM with NAFLD. Conclusion The plasma levels of CHGA and ATGL are closely correlated with substance and energy metabolism, and the interaction between them may play an important role in the pathogenesis of T2DM with NAFLD .

Correlation of free fatty acid and blood lipids in early second trimester and uterine artery notch in pre-eclampsia / 中华围产医学杂志

Objective To analyze the heterogeneous variation of serum free fatty acid (FFA) and lipids during early second trimester in women with or without uterine artery notch in pre-eclampsia (PE).Methods This is a prospective cohort study of 4 000 women with singleton pregnancies registered in early pregnancy and in whom regular check-ups were performed in Haidian Maternal & Child Health Hospital.Blood specimens were collected at gestational age 14-18 weeks at the same time of screening for Down's syndrome.One hundred and one cases with early diastolic notch of the uterine artery were included in the N+ group,and 172 cases without notch but at high risk of PE were included in the N-group at 22-24 weeks.In addition,205 women who were selected randomly at a ratio of 1 ∶ 5,without notch or PE high-risk factors,were also included in the N group.Both groups were subgrouped according to the outcomes of pregnancy complications:early-onset PE group EPE,late-onset PE (LPE),gestational hypertension (GH) group,gestational diabetes mellitus (GDM) group with normal blood pressure,and no complications (NC) group.The variation in FFA and other lipid metabolism indicators in the PE subgroups were compared and analyzed by two independent-sample t-test,one-factor analysis of variance,Chi-square test (or Fisher's exact) and Logistic regression.Results History of PE and pre-hypertension at first visit differed significantly between the N+ and N-groups [3.9％ (4/101) vs.0.8％ (3/377),x2=5.52,P＜0.05; pre-hypertension at first visit,42.2％ (43/101) vs.25.7％ (97/377),x2=10.91,P＜0.05].In the N+ group,23.8％ (n=24) of women had PE,of which 37.5％ (n=8) were early onset.In the N group,2.1％ (n=8) had PE,and all were late onset.The incidence of PE differed significantly between the N+ and N-groups (x2=59.72,P＜0.05).In the N+ group,FFA gradually decreased among the ePE,IPE,GH and NC groups [(0.68±0.27),(0.58±0.21),(0.57±0.21) and (0.49±0.19) mmol/L,F=2.78,P＜0.05]; Multivariate regression analysis showed that FFA (OR=135.68,95％CI:3.78-4 873.00) and PE history (OR=123.25,95％CI:9.27-i 638.00) were risk factors of ePE.Pre-hypertension at registration (OR=4.69,95％CI:2.08-10.58) and pre-pregnancy body mass index (BMI) 24-28 (OR=3.69,95％CI:1.26-10.83) were risk factors ofGH.FFA (OR=9.08,95％CI:2.49-33.01) and pre-pregnancy BMI ≥ 28 (OR=5.08,95％CI:2.16-11.92) were risk factors for GDM.Conclusions Serum FFA and TG levels in early second trimester are correlated with PE,especially the early-onset PE.The onset of PE is heterogeneous and affected by many factors,and occurs in patients with or without early diastolic notch of the uterine artery in the second trimester.Patients with notch are more likely to have early-onset PE,which is correlated with blood FFA and TG levels.

Effects of Puerarin on Glucose, Lipid Metabolism and Gastric Motility in Early Period Type 2 Diabetic Rats / 中国中医药信息杂志

Objective To investigate the effects of Puerarin on glucose and lipid metabolism and gastric motility in early period type 2 diabetic (T2DM) rats.Methods Rat model of T2DM was established by high fat-sugar diet fed and low-dose streptozotocin-treated. SD rats were divided randomly into normal control group (NC), normal+Puerarin group (NP), diabetes control group (DC) and diabetes+Puerarin group (DP). NP and DP rats were given Puerarin 400 mg/(kg?d) once per day for 5 weeks, NC and DC rats were given PBS. Half time of gastric emptying and emptying rate were evaluated by SPECT. The serum level of FBG, GSP, FFA, TC, TG and INS were measured by kit.Results Compared with NC group, DC rats had higher FBG, FFA, TC, GSP, TG and emptying rate, but INS and half time of gastric emptying decreased significantly (P<0.05,P<0.01). Compared with DC group, TG, GSP, FFA and emptying rate of DP rats were reduced (P<0.05), but had more half time of gastric emptying (P<0.05). The results of multivariate stepwise regression analysis showed that FBG related to half time of gastric emptying.Conclusion Type 2 diabetic rats have faster gastric motility, higher blood glucose and lipid. Puerarin might improve the disorders of GSP, TG, FFA and gastric emptying in diabetic rats.

Plasma free fatty acids and risk of heart failure: the Cardiovascular Health Study.

BACKGROUND: Although plasma free fatty acid (FFA) concentrations have been associated with lipotoxicity, apoptosis, and risk of diabetes mellitus and coronary heart disease, it is unclear whether FFA levels are associated with heart failure (HF). METHODS AND RESULTS: To test the hypothesis that plasma concentration of FFAs is positively associated with incident HF, we prospectively analyzed data on 4248 men and women free of HF at baseline and >65 years old from the Cardiovascular Health Study. FFA concentration was measured in duplicate by the Wako enzymatic method. Incident HF was validated by a centralized Events Committee. We used Cox proportional hazards to estimate the hazard ratio of HF per SD of FFAs. During a median follow-up of 10.5 years, a total of 1286 new cases of HF occurred. In a multivariable model adjusting for clinic site, comorbidity, demographic, anthropometric, and lifestyle factors, each SD (0.2 mEq/L) higher plasma FFA was associated with 12% (95% confidence interval, 6%-19%) higher risk of HF. Controlling for time-varying diabetes mellitus and coronary heart disease did not change the results (hazard ratio per SD, 1.16 [95% confidence interval, 1.09-1.23]). CONCLUSIONS: A single measure of plasma FFA obtained later in life is associated with a higher risk of HF in older adults. Additional studies are needed to explore biological mechanisms by which FFAs may influence the risk of HF and determine whether FFAs could serve as a novel pharmacological target for HF prevention.