br Endoplasmic reticulum protein ERp

Endoplasmic reticulum protein 46 (ERp46) binds to AdipoR1 in HeLa cells ERp46 is localized in the ER and is suggested to act as a chaperone. About 20% of endogenous ERp46 are found at the plasma membrane suggesting that this protein may have additional functions. ERp46 interacts with NSC127716 1–70 in the N-terminal tail of AdipoR1. This sequence is not found in AdipoR2 and AdipoR2 does not form a complex with ERp46. Knock-down of ERp46 increases AdipoR1 in the plasma membrane while ER levels are not affected suggesting that ERp46 may regulate AdipoR1 surface abundance by retaining this protein in the ER. Interestingly, ERp46 knock-down also increases AdipoR2 in the ER and plasma membrane fractions by a so far unknown mechanism [64]. In HeLa cells where ERp46 has been knocked-down adiponectin-mediated phosphorylation of AMPK is increased whereas phosphorylation of p38 MAPK is impaired. These findings indicate that activation of AMPK and p38 MAPK are independent downstream effects of adiponectin at least in HeLa cells. It is suggested that ERp46 may have a role in AdipoR1 trafficking and/or endocytosis and this may affect signalling pathways eventually localized to different compartments [64].
Conclusion
Conflict of interest
Acknowledgements The authors thank Prof. Charalampos Aslanidis for helpful suggestions. The research of the authors is supported by the Faculty of Medicine of the University of Regensburg (ReForM C) and by the Deutsche Forschungsgemeinschaft (BU 1141/3-2).
Introduction Metabolic Syndrome is present in an estimated ∼35% of adults in the United States [1], and is a powerful risk factor not only for the future development of type II diabetes but also cardiovascular disease [2], [3], [4]. Metabolic Syndrome, prediabetes, type II diabetes, and cardiovascular disease are linked by a common pathophysiological process that involves insulin resistance, dyslipidemia, and inflammation, and the progression of these diseases constitute the spectrum of cardiometabolic disease. Even so, the factor(s) that is largely responsible for the disparate trait cluster that comprises the Metabolic Syndrome, and the mechanistic link between insulin resistance and vascular disease, have not been fully elucidated. A better understanding of cardiometabolic disease pathophysiology is critical for developing improved modalities for treating and preventing type II diabetes and vascular disease. Adiponectin (also known as apM1, AdipoQ, Gbp28 and Acrp30) is one of several important, metabolically active cytokines secreted from adipose tissue, which circulates in high and low molecular weight multimeric forms [5], [6], [7]. Epidemiological evidence has indicated that plasma adiponectin levels are reduced in patients with insulin resistance, diabetes, obesity, or cardiovascular disease [8], [9], [10], and these relationships are more strongly related to a decrement in the high molecular weight form than the low molecular weight form [6], [7]. In the circulation, adiponectin exerts bioeffects on multiple cell types and has insulin-sensitizing, anti-inflammatory, and anti-atherosclerotic properties. For example, adiponectin has been shown to augment insulin sensitivity and lipid oxidation in skeletal muscle and adipocytes [11], [12] and to reduce hepatic glucose production in liver [13], [14]. Accordingly, administration of adiponectin to intact rodents improved glucose tolerance and decreased plasma triglycerides [11], [12]. In addition, adiponectin can inhibit both the inflammatory process and atherogenesis by suppressing the migration of monocytes/macrophages and their transformation into foam cells in the vascular wall [15], [16]. Transgenic and knockout mouse models have confirmed the importance of adiponectin in metabolic diseases. Overexpression of the adiponectin gene protected ob/ob mice from diabetes and prevented apolipoprotein E-deficient mice from developing atherosclerosis [17]. Furthermore, overexpression of adiponectin in fat tissues resulted in increased circulating adiponectin levels, which in turn led to improved insulin sensitivity [18], [19]. There is also evidence that adiponectin gene polymorphisms may be associated with hypoadiponectinemia, together with insulin resistance and type II diabetes [20].