Overexpression of Angiopoietin-Like Protein 4 Alters Mitochondria Activities and Modulates Methionine Metabolic Cycle in the Liver Tissues of db/db Diabetic Mice

Wang, Yudong; Lam, Karen S.L.; Lam, Janice; Lam, Michael C.; Leung, Priscilla T.Y.; Zhou, Mingyan; Xu, Aimin

doi:10.1210/me.2006-0249

Cited by 42 publications

(29 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These discrepancies between liver mitochondrial adaptive responses to obesity and insulin resistance could be due to several factors, including experimental design, age, genetic background, and species differences (10). However, using two-dimensional differential electrophoresis, dysregulated proteins in liver from db/db mice were localized in mitochondria, corresponding to decreased activity of mitochondrial complex I-V enzymes (48), in agreement with our present observations. Moreover, our findings are also consistent with earlier studies of white adipose tissue from db/db and ob/ob mice showing reduced mitochondrial respiration and fatty acid oxidation.…”

Section: E735supporting

confidence: 85%

“…Mitochondria are finely tuned to meet the specific needs of the tissue as well as the environmental or pathophysiological state that the specific tissue encounters (1). Thus, obesity and T2DM may be accompanied by tissuespecific differences in the mitochondrial profile.Several lines of evidence suggest that mitochondrial function in liver or skeletal muscle is associated with insulin sensitivity and T2DM in animal models (2,10,12,20,40,48) and humans (25, 27, 36 -39). Yet differences in methodology, experimental design, age, genetic background, and sex of the animals/individuals under investigation may independently influence mitochondrial function.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Tissue-specific control of mitochondrial respiration in obesity-related insulin resistance and diabetes

Holmström

Iglesias‐Gutiérrez

Zierath

et al. 2012

American Journal of Physiology-Endocrinology and Metabolism

120

View full text Add to dashboard Cite

The tissue-specific role of mitochondrial respiratory capacity in the development of insulin resistance and type 2 diabetes is unclear. We determined mitochondrial function in glycolytic and oxidative skeletal muscle and liver from lean (ϩ/?) and obese diabetic (db/db) mice. In lean mice, the mitochondrial respiration pattern differed between tissues. Tissuespecific mitochondrial profiles were then compared between lean and db/db mice. In liver, mitochondrial respiratory capacity and protein expression, including peroxisome proliferator-activated receptor-␥ coactivator-1␣ (PGC-1␣), was decreased in db/db mice, consistent with increased mitochondrial fission. In glycolytic muscle, mitochondrial respiration, as well as protein and mRNA expression of mitochondrial markers, was increased in db/db mice, suggesting increased mitochondrial content and fatty acid oxidation capacity. In oxidative muscle, mitochondrial complex I function and PGC-1␣ and mitochondrial transcription factor A (TFAM) protein levels were decreased in db/db mice, along with increased level of proteins related to mitochondrial dynamics. In conclusion, mitochondrial respiratory performance is under the control of tissue-specific mechanisms and is not uniformly altered in response to obesity. Furthermore, insulin resistance in glycolytic skeletal muscle can be maintained by a mechanism independent of mitochondrial dysfunction. Conversely, insulin resistance in liver and oxidative skeletal muscle from db/db mice is coincident with mitochondrial dysfunction. mitochondrial dysfunction; mitochondrial biogenesis; oxidative capacity; energy metabolism OBESITY IS A MAJOR RISK FACTOR for development of insulin resistance and type 2 diabetes mellitus (T2DM) (49). Insulin resistance in skeletal muscle and liver, coupled with ␤-cell failure, represents underlying defects in T2DM. Thus, there is a growing appreciation that defects in insulin action in multiple tissues contribute to whole body insulin resistance, disturbances in energy balance, and T2DM.Mitochondrial dysfunction has been implicated in the development of insulin resistance and the pathogenesis of T2DM (32,37,38). The vast majority of mitochondrial proteins, as well as factors controlling the expression and proliferation of the mitochondrial genome, are encoded in the nucleus. Studies of rodent tissues, including analysis of mitochondrial DNA copy number, cytochrome c oxidase activity, and mitochondrial mass in liver, cardiac muscle, and oxidative and glycolytic skeletal muscle (8,9,14,50,51) provide evidence for marked tissue-specific differences in mitochondrial properties, concurrent with varying metabolic characteristics and demands unique to each specific tissue. Furthermore, quantitative mass spectrometry and 2-D gel electrophoresis of the mitochondrial proteome reveal tissue-specific mitochondrial protein programs (13,24,34). Mitochondria are finely tuned to meet the specific needs of the tissue as well as the environmental or pathophysiological state that the specific tissue encounters (1...

show abstract

Section: E735supporting

confidence: 85%

mentioning

confidence: 99%

Tissue-specific control of mitochondrial respiration in obesity-related insulin resistance and diabetes

Holmström

Iglesias‐Gutiérrez

Zierath

et al. 2012

American Journal of Physiology-Endocrinology and Metabolism

120

View full text Add to dashboard Cite

show abstract

“…Expression and Purification of Recombinant MUP-1 in Escherichia coli-cDNA from the male mouse liver was used as the template for cloning the gene encoding full-length MUP-1, which does not include the secretory signal peptide (amino acids [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18]. The primer sequences used for cloning were 5Ј-CCGCTGGATCCGAAGAAGC TAGTTCTACGG-3Ј (forward) and 5Ј-ACTGTC TCGAGTCATTCTCGGGCCTG-GAGG-3Ј (reverse), respectively.…”

Section: Methodsmentioning

confidence: 99%

Major Urinary Protein-1 Increases Energy Expenditure and Improves Glucose Intolerance through Enhancing Mitochondrial Function in Skeletal Muscle of Diabetic Mice

Hui

Zhu²,

Wang³

et al. 2009

Journal of Biological Chemistry

Self Cite

115

147

View full text Add to dashboard Cite

Major urinary protein-1 (MUP-1) is a low molecular weight secreted protein produced predominantly from the liver. Structurally it belongs to the lipocalin family, which carries small hydrophobic ligands such as pheromones. However, the physiological functions of MUP-1 remain poorly understood. Here we provide evidence demonstrating that MUP-1 is an important player in regulating energy expenditure and metabolism in mice. Both microarray and real-time PCR analysis demonstrated that the MUP-1 mRNA abundance in the liver of db/db obese mice was reduced by ϳ30-fold compared with their lean littermates, whereas this change was partially reversed by treatment with the insulin-sensitizing drug rosiglitazone. In both dietary and genetic obese mice, the circulating concentrations of MUP-1 were markedly decreased compared with the lean controls. Chronic elevation of circulating MUP-1 in db/db mice, using an osmotic pump-based protein delivery system, increased energy expenditure and locomotor activity, raised core body temperature, and decreased glucose intolerance as well as insulin resistance. At the molecular level, MUP-1-mediated improvement in metabolic profiles was accompanied by increased expression of genes involved in mitochondrial biogenesis, elevated mitochondrial oxidative capacity, decreased triglyceride accumulation, and enhanced insulin-evoked Akt signaling in skeletal muscle but not in liver. Altogether, these findings raise the possibility that MUP-1 deficiency might contribute to the metabolic dysregulation in obese/diabetic mice, and suggest that the beneficial metabolic effects of MUP-1 are attributed in part to its ability in increasing mitochondrial function in skeletal muscle.The liver is the primary organ for carbohydrate and lipid metabolism, including gluconeogenesis, glycogenesis, cholesterol biosynthesis, and lipogenesis (1, 2). These metabolic events in the liver are tightly controlled by several pancreatic hormones including insulin and glucagon. In addition, the liver itself is one of the largest endocrine organs in the body, secreting numerous humoral factors involved in the regulation of systemic glucose and lipid homeostasis. The importance of the liver-derived humoral factors in maintaining glucose metabolism is highlighted by the observation that glucose uptake by skeletal muscle is severely impaired by surgical or pharmacological blockade of hepatic parasympathetic nerves (3). In the past several years, a number of liver-derived humoral metabolic factors, including bone morphogenetic protein-9 (BMP-9) (4), fibroblast growth factor 21 (FGF21) (5-7), retinol-binding protein 4 (RBP4) (8, 9), adropin (10), and angiopoietin-like proteins (Angptl) 3, 4, and 6 (11-13), have been identified, and their roles in glucose and lipid metabolism have been characterized in great detail. Noticeably, BMP-9, FGF21, and Angptl6 exhibit potent insulin-sensitizing and glucose-lowering effects in animal models, and they have been proposed as potential candidates for the treatment of insulin resistance and ty...

show abstract

“…In fact, this could explain why there is no signifi cant decrease of ANGPLT4 in overweight subjects over 45 years old as observed in overweight subjects under 45 years old. The inverse relationship of ANGPTL4 with Hcy is not surprising as ANGPTL4 was shown to decrease key enzymes in the methionine/Hcy metabolic cycle ( 34 ). The positive correlation with CRP suggests that infl ammatory processes may be connected to increased ANGPTL4 levels in humans.…”

Section: Effect Of Heparin On Human Angptl 3 and 4 In Vivo And In Vitromentioning

confidence: 97%

Quantitation of serum angiopoietin-like proteins 3 and 4 in a Finnish population sample

Robciuc

Tahvanainen

Jauhiainen

et al. 2010

Journal of Lipid Research

View full text Add to dashboard Cite

Dysregulation of lipid metabolism is closely related with a number of pathological states including atherosclerosis, obesity, and insulin resistance. An extensive amount of data relates elevation of cholesterol and triglycerides (TG) in apolipoprotein (apo)B-containing particles such as VLDL and LDL to increased risk for atherosclerosis. Epidemiological and clinical studies have provided strong evidence that a low level of cholesterol in HDL is also a major risk factor for the development of atherosclerosis ( 4, 5 ). LPL is a key molecule involved in the hydrolysis of TG in VLDL and chylomicrons and in the clearance of these particles from circulation ( 6 ). In vitro observations as well as animal models have fi rmly established ANGPTL 3 and 4 as potent inhibitors of LPL ( 7,8 ). These studies are supported by genetic studies in humans that have associated mutations in these two proteins with circulating TG levels ( 9-11 ). Endothelial lipase (EL), a member of the triglyceride lipase gene family, has been demonstrated to infl uence the levels of HDL in circulation ( 12 ). Recently, it was shown that ANGPTL3 can inhibit EL and thereby increase the levels of HDL ( 13 ).Epidemiological studies clearly demonstrate that obesity has increased worldwide. Obesity increases the risk of diabetes, heart disease, fatty liver, and even some forms of cancer. It is therefore important to better understand the biological basis of obesity in order to aid its prevention and treatment. Several studies in mice have shown that ANGPTL4 can act as a powerful signal from adipose and other tissues to prevent fat storage and stimulate fat mobilization ( 14, 15 ). There is a large body of evidence demonstrating that ANGPTL 3 and 4 play major roles in rodent energy metabolism. However, there is limited information on the physiological roles of ANGPTL 3 and 4 in humans. The anthropometric and biochemical parameters of subjects were characterized in detail. ANGPTL 3 and 4 levels were determined using the developed ELISAs. The intraand inter-assay coeffi cients of variation for the assays were less than 15%. The average serum concentration of ANGPTL3 was 368 ± 168 ng/ml (mean ± SD) and for ANGPTL4 it was 18 ± 23 ng/ml (mean ± SD). ANGPTL4 serum levels displayed high variability between individuals ranging from 2 to 158 ng/ml. In post-heparin plasma, both ANGPTL 3 and 4 were increased. Low levels of ANGPTL3 were associated with decreased HDL-cholesterol and increased triglyceride levels. ANGPTL4 levels were positively correlated with FFAs ( P = 0.044) and waist-hip ratio ( P = 0.016). The developed ELISAs will be important tools to clarify the role of ANGPTL 3 and 4 in human energy metabolism and partitioning of triglycerides between sites of storage (adipose tissue) and oxidation (skeletal and cardiac muscle). Angiopoietin-like (ANGPTL) proteins 3 and 4 belong to a family of proteins that share a common modular structure consisting of an N-terminal signal sequence, a coiledcoil domain and a large fi brinogen/angiopoietin-like domain ( 1, 2 ...

show abstract

Overexpression of Angiopoietin-Like Protein 4 Alters Mitochondria Activities and Modulates Methionine Metabolic Cycle in the Liver Tissues of db/db Diabetic Mice

Cited by 42 publications

References 49 publications

Tissue-specific control of mitochondrial respiration in obesity-related insulin resistance and diabetes

Tissue-specific control of mitochondrial respiration in obesity-related insulin resistance and diabetes

Major Urinary Protein-1 Increases Energy Expenditure and Improves Glucose Intolerance through Enhancing Mitochondrial Function in Skeletal Muscle of Diabetic Mice

Quantitation of serum angiopoietin-like proteins 3 and 4 in a Finnish population sample

Contact Info

Product

Resources

About