Soluble LR11/SorLA represses thermogenesis in adipose tissue and correlates with BMI in humans.

Thermogenesis in brown adipose tissue (BAT) is an important component of energy expenditure in mammals. Recent studies have confirmed its presence and metabolic role in humans. Defining the physiological regulation of BAT is therefore of great importance for developing strategies to treat metabolic diseases. Here we show that the soluble form of the low-density lipoprotein receptor relative, LR11/SorLA (sLR11), suppresses thermogenesis in adipose tissue in a cell-autonomous manner. Mice lacking LR11 are protected from diet-induced obesity associated with an increased browning of white adipose tissue and hypermetabolism. Treatment of adipocytes with sLR11 inhibits thermogenesis via the bone morphogenetic protein/TGFβ signalling pathway and reduces Smad phosphorylation. In addition, sLR11 levels in humans are shown to positively correlate with body mass index and adiposity. Given the need for tight regulation of a tissue with a high capacity for energy wastage, we propose that LR11 plays an energy conserving role that is exaggerated in states of obesity.AW and AVP were supported by FP7 – BetaBAT, BBSRC (BB/J009865/1), the British Heart Foundation (PG/12/53/29714) and MDU MRC. MJ and HB were supported by Japan Health and Labour Sciences Research grant (H22-rinkensui-ippan-001) and Grants-in–aid for Scientific Research from Japanese Ministry of Education, Culture, Sports, Science and Technology (24390231 and 24790907). VP was supported by Wellcome Trust and the Cambridge Overseas Trust. JR was supported by Ministerio de Educación, through “Programa Nacional de Movilidad de Recursos Humanos del Plan Nacional de I-D+i 2008-2011 (Subprograma de Estancias de Movilidad en el Extranjero “José Castillejo” para jóvenes Doctores, ref: JC2011-0248). SV was supported by MRC. WJS was supported by the Austrian Science Fund (FWF P-20218 and P-20455). Animal work was performed at the MDU DMC Core facilities.This is the final version of the article. It first appeared from NPG via http://dx.doi.org/10.1038/ncomms995

Soluble LR11/SorLA represses thermogenesis in adipose tissue and correlates with BMI in humans

Thermogenesis in brown adipose tissue (BAT) is an important component of energy expenditure in mammals. Recent studies have confirmed its presence and metabolic role in humans. Defining the physiological regulation of BAT is therefore of great importance for developing strategies to treat metabolic diseases. Here we show that the soluble form of the low-density lipoprotein receptor relative, LR11/SorLA (sLR11), suppresses thermogenesis in adipose tissue in a cell-autonomous manner. Mice lacking LR11 are protected from diet-induced obesity associated with an increased browning of white adipose tissue and hypermetabolism. Treatment of adipocytes with sLR11 inhibits thermogenesis via the bone morphogenetic protein/TGFb signalling pathway and reduces Smad phosphorylation. In addition, sLR11 levels in humans are shown to positively correlate with body mass index and adiposity. Given the need for tight regulation of a tissue with a high capacity for energy wastage, we propose that LR11 plays an energy conserving role that is exaggerated in states of obesity

Preheparin serum lipoprotein lipase mass level: the effects of age, gender, and types of hyperlipidemias. Atherosclerosis

Abstract To clarify the clinical implication of preheparin serum lipoprotein lipase mass (preheparin LpL mass), we studied the relationships between preheparin LpL mass and serum lipids, including midband lipoproteins, which migrate between very low density lipoproteins and low density lipoproteins on polyacrylamide gel disc electrophoresis, in hyperlipidemias. And we also studied the changes of preheparin LpL mass in hypertriglyceridemic patients during bezafibrate administration, which is known to enhance LpL activity in postheparin plasma. Preheparin LpL mass correlated positively with high-density lipoprotein-cholesterol (HDL-C) (r = 0.418, P B0.01) and negatively with triglyceride (TG) (r= −0.256, PB 0.01), but did not correlate with total cholesterol (TC) in 64 hyperlipidemic (type IIa, IIb and IV) patients. The midband lipoproteins were observed in 80% of hypertriglyceridemic patients (32/40). Preheparin LpL mass in midband lipoprotein-positive subjects was lower significantly than that in midband-negative subjects. When bezafibrate (400 mg/day) was administrated to 40 hypertriglyceridemic patients for 4 months, TG level significantly decreased ( − 499 7%, P B0.01), TC levels decreased ( − 1194%, not significant), and HDL-C levels increased ( +2794%, PB0.01). The midband lipoproteins disappeared in 95% of patients. Preheparin LpL mass significantly increased ( +2596%, P B0.0005). In nine patients who stopped bezafibrate, TG levels significantly increased ( +49 97%, PB 0.01) and HDL-C levels decreased (−2794%, PB 0.01). Preheparin LPL mass significantly decreased (− 2596%, PB 0.0005). These results suggested that bezafibrate administration enhanced preheparin LpL mass. And it might be implicated that enhanced LpL production by bezafibrate could reflect an increase of preheparin LpL mass

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 0.05). Multiple linear regression analysis identified increasing the dose of metformin treatment as the only independent factor associated with decreased MDA-LDL (β 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