Adipocyte-specific Tribbles Pseudokinase 1 Regulates Plasma Adiponectin and Plasma Lipids in Mice

Tribbles-1 (TRIB1) was recently identified through genome-wide association studies as a novel mediator of plasma lipids and coronary artery disease in humans. While subsequent in vivo mouse work confirmed a role for hepatic TRIB1 in these associations, little is known about metabolic roles for extra-hepatic Trib1. Interestingly, SNPs near the TRIB1 gene are significantly associated with circulating adiponectin levels in humans, suggesting a metabolic role for adipose TRIB1 . To further investigate this, we generated adipose-specific Trib1 KO mice (Trib1_ASKO) by crossing Trib1 cKO mice to transgenic Adiponectin-Cre mice. Chow-fed Trib1_ASKO mice exhibited no differences in adipose tissue mass and overall body mass as compared to control littermates (N=8/group). However, Trib1_ASKO mice had reduced total (-16.9%, p <0.01), HDL (-16.7%, p <0.01), and non-HDL cholesterol (-17.3%, p =0.068), as well as plasma triglycerides (-28.6%, p <0.001) as compared to WT mice. Trib1_ASKO mice also had increased plasma adiponectin levels, a finding more pronounced in female mice (+33.3%, p <0.001) than in males (+16.4%, p =0.072). Despite this increase, transcript levels of adipoQ were moderately decreased in Trib1_ASKO mice, suggesting a post-transcriptional mode of regulation. Transcript and protein levels of C/EBPα, the best described target of Trib1 and a key regulator of adipogenesis, remained unchanged. To further investigate the metabolic consequences of adipose-specific KO of Trib1 , WT and Trib1_ASKO mice were fed high-fat diet (HFD, 45% kCal fat) for 12 weeks to induce obesity. HFD-fed Trib1_ASKO mice had reduced fasting plasma glucose (-22.3%, p <0.05), insulin (-38.2%, p <0.05), and glucose tolerance (-19.8% AUC, p <0.05) compared to control mice. Body mass and fat mass of HFD-fed Trib1_ASKO mice remained unchanged from WT, and the reductions in plasma lipids and increase in plasma adiponectin persisted in the HFD-fed state. In summary, we present here the first in vivo validation of the human genetic association between TRIB1 and plasma adiponectin, and provide evidence suggesting that adipose TRIB1 contributes to the genetic associations observed in humans between TRIB1 and multiple metabolic parameters.

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Plasma adiponectin and serum advanced glycated end-products increase and plasma lipid concentrations decrease with increasing duration of type 2 diabetes

Acta Endocrinologica ◽

10.1530/eje.0.1510361 ◽

2004 ◽

pp. 361-366 ◽

Cited By ~ 13

Author(s):

A Gottsater ◽

B Szelag ◽

M Kangro ◽

M Wroblewski ◽

G Sundkvist

Keyword(s):

Plasma Lipids ◽

Density Lipoprotein ◽

Diabetic Patients ◽

Type 2 Diabetic Patients ◽

C Peptide ◽

Plasma Adiponectin ◽

End Products ◽

Type 2 Diabetic

OBJECTIVE: To prospectively follow the concentrations of plasma adiponectin (p-adiponectin) and serum advanced glycation end-products (s-AGE) in relation to plasma lipids and retinopathy over 3 years in type 2 diabetic patients. DESIGN AND METHODS: P-adiponectin, s-AGE, plasma lipids and diabetic retinopathy were prospectively evaluated in 61 type 2 diabetic patients at baseline and at follow up 3 years later. RESULTS: Mean p-adiponectin (from 8.84+/-5.14 to 11.05+/-6.16 microg/ml; P=0.006) and s-AGE (from 637+/-242 to 781+/-173 ng/ml; P<0.0001) concentrations had increased at follow up. In addition, HbA1c (7.7+/-1.7 to 7.4+/-1.4%; P=0.0045) and fasting C-peptide (1.00+/-0.38 to 0.81+/-0.35 nM; P=0.019) had decreased and all lipid variables had significantly improved at follow up. P-adiponectin correlated inversely with fasting C-peptide (r(s)=-0.273; P=0.045) and low-density lipoprotein (LDL)/high-density lipoprotein (HDL) ratio (r(s)=-0.362; P=0.011), and directly with plasma HDL cholesterol (r(s)=0.381; P=0.005) at follow up. Analysis of variance with adiponectin and s-AGE as dependent variables and fasting C-peptide, plasma HDL and plasma LDL cholesterol as covariates demonstrated that the increase in s-AGE was independent (P=0.001) and the increase in p-adiponectin dependent on covariate changes (P=0.862). There was a slight correlation between s-AGE at baseline versus the degree of retinopathy at follow up (r(s)=0.281; P=0.0499). CONCLUSION: Both p-adiponectin and s-AGE increased during the 3 years. The increase in p-adiponectin was explained by improvements in insulin sensitivity and dyslipidaemia, whereas the increase in s-AGE was independent of changes in metabolic covariates. s-AGE increase when the duration of type 2 diabetes increases.

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Adipocyte Tribbles1 Regulates Plasma Adiponectin and Plasma Lipids in Mice

10.1101/2021.03.11.434882 ◽

2021 ◽

Author(s):

Elizabeth E. Ha ◽

Gabriella I. Quartuccia ◽

Ruifeng Ling ◽

Chenyi Xue ◽

Antonio Hernandez-Ono ◽

...

Keyword(s):

Coronary Artery Disease ◽

Adipose Tissue ◽

Coronary Artery ◽

Plasma Lipids ◽

Plasma Cholesterol ◽

Rna Seq ◽

Genetic Associations ◽

Fluorescent Substrate ◽

Plasma Adiponectin ◽

Artery Disease

AbstractMultiple GWAS have identified SNPs in the 8q24 locus near the TRIB1 gene that significantly associate with plasma lipids and coronary artery disease. While subsequent studies have uncovered roles for hepatic and myeloid Trib1 in contributing to either plasma lipids or atherosclerosis, the causal tissue for these GWAS associations remains unclear. The same 8q24 SNPs significantly associate with plasma adiponectin levels in humans as well, suggesting a role for TRIB1 in adipose tissue. Here, we report that adipocyte-specific Trib1 knockout mice (Trib1_ASKO) have increased plasma adiponectin levels and decreased plasma cholesterol and triglycerides. We demonstrate that loss of Trib1 increases adipocyte production and secretion of adiponectin independent of the known TRIB1 function of regulating proteasomal degradation. RNA-seq analysis of adipocytes and livers from Trib1_ASKO mice suggests that alterations in adipocyte function underlie the plasma lipid changes observed in these mice. Secretomics and RNA-seq analysis revealed that Trib1_ASKO mice have increased production of Lpl and decreased production of Angptl4 in adipose tissue, and fluorescent substrate assays confirm an increase in adipose tissue Lpl activity, which likely underlies the observed triglyceride phenotype. In summary, we demonstrate here a novel role for adipocyte Trib1 in regulating plasma adiponectin, total cholesterol, and triglycerides in mice, confirming previous genetic associations observed in humans and providing a novel avenue through which Trib1 regulates plasma lipids and coronary artery disease.

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Experimental Pancreatitis and Plasma Lipids

Gastroenterology ◽

10.1016/s0016-5085(19)35496-4 ◽

1958 ◽

Vol 35 (5) ◽

pp. 465-472 ◽

Cited By ~ 26

Author(s):

C. Wang ◽

L. Strauss ◽

D. Adlersberg

Keyword(s):

Plasma Lipids ◽

Experimental Pancreatitis

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W09.217 Association between plasma adiponectin levels and adipose tissue compartments in men

Atherosclerosis ◽

10.1016/s0021-9150(04)90216-x ◽

2004 ◽

Vol 5 (1) ◽

pp. 50-51

Author(s):

M FARVID

Keyword(s):

Adipose Tissue ◽

Plasma Adiponectin ◽

Tissue Compartments

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Cardioprotective Effects of Diet with Different Grains on Lipid Profiles and Antioxidative System in Obesity-Induced Rats

International Journal for Vitamin and Nutrition Research ◽

10.1024/0300-9831/a000097 ◽

2012 ◽

Vol 82 (2) ◽

pp. 85-93 ◽

Cited By ~ 9

Author(s):

Y. Kim ◽

H. Shin ◽

S. Lee

Keyword(s):

Aortic Wall ◽

Plasma Lipids ◽

Antioxidant Activities ◽

Plasma Lipid ◽

Density Lipoprotein ◽

Thiobarbituric Acid ◽

Lipid Profiles ◽

Dietary Lipids ◽

Male Rats

In the present study, the nutritional quality of four grains including adlay (AD), buckwheat (BW), glutinous barley (GB), and white rice (WR) were evaluated in terms of plasma lipid parameters, gut transit time, and thickness of the aortic wall in rats. The rats were then raised for 4 weeks on the high-fat diet based on the American Institute of Nutrition-93 (AIN-93 G) diets containing 1 % cholesterol and 20 % dietary lipids. Forty male rats were divided into 4 groups and raised for 4 weeks with a diet containing one of the following grains: WR, AD, BW, or WB. The level of thiobarbituric acid-reactive substances (TBARS) in liver was shown to be higher in rats by the order of those fed WR, AD, GB, and BW. This indicates that other grains decreased oxidative stress in vivo more than WR. The superoxide dismutase, glutathione, glutathione peroxidase, and glutathione reductase levels in the AD, BW, and GB groups were significantly higher than those in the WR group (p < 0.05). Plasma lipid profiles differed significantly according to grain combination, and decreased aortic wall thickness was consistent with the finding of decreased plasma low-density lipoprotein cholesterol (LDL-C) (p < 0.05) and increased high-density lipoprotein (HDL-C) in rats fed AD, BW, and GB (p < 0.001). The antioxidant and hypolipidemic capacities of grains are quite high, especially those of adlay, buckwheat, and glutinous barley. In conclusion, this study has demonstrated that the whole grains had a cardioprotective effect. This effect was related to several mechanisms that corresponded to lowering plasma lipids, decreasing TBARS, and increasing antioxidant activities.

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The Effect of n-3 Fatty Acids on Lipids and Haemostasis in Patients with Type lla and Type IV Hyperlipidaemia

Thrombosis and Haemostasis ◽

10.1055/s-0038-1646906 ◽

1989 ◽

Vol 62 (02) ◽

pp. 797-801 ◽

Cited By ~ 24

Author(s):

E Berg Schmidt ◽

E Ernst ◽

K Varming ◽

J O Pedersen ◽

J Dyerberg

Keyword(s):

Fatty Acids ◽

Plasma Lipids ◽

Plasma Cholesterol ◽

Hdl Cholesterol ◽

Apolipoprotein A1 ◽

Type Iv ◽

Before And After ◽

Von Willebrand ◽

Willebrand Factor ◽

Factor Antigen

SummaryPlasma lipids and haemostasis were investigated in 17 patients with hyperlipidaemia before and after 6 weeks supplementation with 6 g n-3 fatty acids. Nine of the patients had type IIa and 8 had type IV hyperlipidaemia. No effect on plasma cholesterol, LDL- or HDL-cholesterol were seen, but plasma triglycerides decreased after n-3 supplementation. Apolipoprotein B increased and apolipoprotein A1 decreased after the oil supplement. The bleeding time was prolonged, but platelet aggregation was unaltered by n-3 fatty acids. Protein C activity increased in type II a and decreased in type IV after the supplement. Fibrinolysis was markedly depressed while von Willebrand factor antigen was reduced after intake of n-3 fatty acids.

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Increased Activity of Vitamin K-Dependent Clotting Factors in Human Hyperlipoproteinaemia – Association with Cholesterol and Triglyceride Levels

Thrombosis and Haemostasis ◽

10.1055/s-0038-1651852 ◽

1977 ◽

Vol 38 (02) ◽

pp. 0465-0474 ◽

Cited By ~ 46

Author(s):

M Constantino ◽

C Merskey ◽

D. J Kudzma ◽

M. B Zucker

Keyword(s):

Vitamin K ◽

Plasma Lipids ◽

Coagulation Factors ◽

Clotting Factor ◽

Factor X ◽

Clotting Factors ◽

Blood Coagulation Factors ◽

Cholesterol Levels ◽

Type V ◽

Increased Activity

SummaryLevels of blood coagulation factors, cholesterol and triglyceride were measured in human plasma. Prothrombin was significantly elevated in type Ha hyperlipidaemia; prothrombin and factors VII, IX and X in type lib; and prothrombin and factors VII and IX in type V. Multiple regression analysis showed significant correlation between the levels of these plasma lipids and the vitamin K-dependent clotting factors (prothrombin, factors VII, IX and X). Higher cholesterol levels were associated with higher levels of prothrombin and factor X while higher triglyceride levels were associated with higher levels of these as well as factors VII and IX. Prothrombin showed a significant cholesterol-triglyceride interaction in that higher cholesterol levels were associated with higher prothrombin levels at all levels of triglyceride, with the most marked effects in subjects with higher triglyceride levels. Higher prothrombin levels were noted in subjects with high or moderately elevated (but not low) cholesterol levels. Ultracentrifugation of plasma in a density of 1.21 showed activity for prothrombin and factors VII and X only in the lipoprotein-free subnatant fraction. Thus, a true increase in clotting factor protein was probably present. The significance of the correlation between levels of vitamin K-dependent clotting factors and plasma lipids remains to be determined.

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Dihomo-γ-Linolenic Acid in Patients with Atherosclerosis: Effects on Platelet Aggregation, Plasma Lipids and Low-Density Lipoprotein-Induced Inhibition of Prostacyclin Generation

Thrombosis and Haemostasis ◽

10.1055/s-0038-1661054 ◽

1984 ◽

Vol 51 (02) ◽

pp. 186-188 ◽

Cited By ~ 11

Author(s):

A Szczeklik ◽

R J Gryglewski ◽

K Sladek ◽

E Kostka-Trąbka ◽

A Żmuda

Keyword(s):

Linolenic Acid ◽

Plasma Lipids ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Thromboxane A2 ◽

Low Density ◽

Red Cell ◽

Double Blind ◽

Daily Dose ◽

Antithrombotic Effects

SummaryDihomo-γ-linolenic acid (DHLA), a precursor of monoenoic anti-aggregatory prostaglandins (PGE1, PGD2), was administered for 4 weeks in a daily dose of 1.0 g into 33 patients with atherosclerosis on a basis of a double-blind trial. Comparison of treatment and placebo groups revealed elevation of DHLA in red cell lipids in DHLA-treated subjects. No differences, however, between the two groups could be observed in platelet aggregability, thromboxane A2 generation by platelets, serum cholesterol, PGE1 and PGE2 levels, and in inhibitory activity of low-density lipoproteins against prostacyclin synthetizing system in arteries. The dietary supplementation used did not lead to distinct antithrombotic effects.

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