The role of apolipoprotein A5 in obesity and the metabolic syndrome

Apolipoprotein A5 (apoA5) has an important role in lipid metabolism, specifically for triglyceride‐rich lipoproteins. Recently, evidence has emerged for an association between genetic variability at the APOA5 locus and increased risk of obesity and metabolic syndrome. However, its mechanism of action remains to be fully elucidated. Importantly, an intracellular role of apoA5 has been indicated since apoA5 is associated with cytoplasmic lipid droplets and affects intrahepatic triglyceride accumulation, as well as affecting intravascular triglyceride metabolism. Given that adipocytes provide the largest storage depot for energy in the form of triglyceride within the lipid droplets, and play a crucial role in the development of obesity, we highlight recent findings discussing the interaction of apoA5 with adipocytes or adipose tissue, indicating that apoA5 may act as a novel regulator to modulate triglyceride storage in adipocytes. We review the association of APOA5 gene polymorphisms with obesity and metabolic syndrome, and propose potential mechanisms by which apoA5 may increase susceptibility to these conditions. This review provides new insights into the physiological role of apoA5 and identifies a potential therapeutic target for obesity and associated disorders.     

On the structure and function of apolipoproteins: more than a family of lipid-binding proteins

Exchangeable apolipoproteins have been the subject of intense biomedical investigation for decades. However, only in recent years the elucidation of the three-dimensional structure reported for several members of the apolipoprotein family has provided insights into their functions at a molecular level for the first time. Moreover, the role of exchangeable apolipoproteins in several cellular events distinct from lipid metabolism has recently been described. This review summarizes these contributions, which have not only allowed the identification of the apolipoprotein domains that determine substrate binding specificity and/or affinity but also the plausible molecular mechanism(s) involved.     

Apolipoprotein A5 internalized by human adipocytes modulates cellular triglyceride content

Apolipoprotein A5 (apoA5), an important determinant of plasma triglyceride (TG) levels, has been recently reported to modulate TG metabolism in hepatocytes. In this study, we investigated whether apoA5 can be internalized by adipocytes and regulate cellular TG storage. Human preadipocytes, derived from subcutaneous adipose tissue of patients undergoing abdominal surgery, were differentiated into mature adipocytes. Pulse-chase experiments revealed that apoA5 was internalized into human adipocytes, and ～70% of the apoA5 internalized during the pulse remained intracellular within a 24-h chase, while 30% was degraded. Preincubation with heparin and the receptor-associated protein, both of which prevented the apoA5 interaction with members of the low-density lipoprotein receptor gene family, markedly reduced the uptake of apoA5 by 61% and 52%, respectively, which were subsequently confirmed by Western blot analysis. Using confocal microscopy, we demonstrated that labeled apoA5 surrounded lipid droplets in human adipocytes and colocalized with the known lipid droplet protein perilipin. Importantly, treatment of adipocytes with apoA5 significantly decreased cellular TG storage. In conclusion, apoA5 can be internalized by human adipocytes and may act as a novel regulator to control TG storage in human adipocytes.     

Autophagy: Emerging roles in lipid homeostasis and metabolic control

Current evidence implicates autophagy in the regulation of lipid stores within the two main organs involved in maintaining lipid homeostasis, the liver and adipose tissue. Critical to this role in hepatocytes is the breakdown of cytoplasmic lipid droplets, a process referred to as lipophagy. Conversely, autophagy is required for adipocyte differentiation and the concurrent accumulation of lipid droplets. Autophagy also affects lipid metabolism through contributions to lipoprotein assembly. A number of reports have now implicated autophagy in the degradation of apolipoprotein B, the main structural protein of very-low-density-lipoprotein. Aberrant autophagy may also be involved in conditions of deregulated lipid homeostasis in metabolic disorders such as the metabolic syndrome. First, insulin signalling and autophagy activity appear to diverge in a mechanism of reciprocal regulation, suggesting a role for autophagy in insulin resistance. Secondly, upregulation of autophagy may lead to conversion of white adipose tissue into brown adipose tissue, thus regulating energy expenditure and obesity. Thirdly, upregulation of autophagy in hepatocytes could increase breakdown of lipid stores controlling triglyceride homeostasis and fatty liver. Taken together, autophagy appears to play a very complex role in lipid homeostasis, affecting lipid stores differently depending on the tissue, as well as contributing to pathways of lipoprotein metabolism.     

Apolipoprotein A5, a unique modulator of fasting and postprandial triglycerides

The discovery of apolipoprotein A5 (APOA5) in 2001 has raised a number of intriguing questions about its role in lipid transport and triglyceride (TG) homeostasis. Genome-wide association studies have consistently identified APOA5 as a regulator of plasma TG levels, which is further supported by studies in transgenic and knockout mouse models. The present review describes recent concepts pertaining to the roles of APOA5 in TG metabolism as related to the vascular compartment, liver, adipose tissue and the gut. Recent evidence indicates that APOA5 may also affect postprandial TG metabolism through influencing chylomicron formation and transport by the intestine into the intestinal lymph. While substantial evidence supports the notion that APOA5 plays both extracellular and intracellular roles in TG homeostasis, mysteries remain on how this low-abundance, liver-derived protein may modulate TG homeostasis, including via the gut. Given the strong correlation between elevated plasma TG and cardiometabolic diseases, there is great scientific and public interest in understanding the intriguing mysteries presented by APOA5.     

敲除Adipophilin基因对脂质代谢相关疾病的作用

Adipophilin是PAT (perilipin/adipophilin/Tip47)蛋白家族的一个成员,定位于细胞质和细胞内的脂滴表面.Adipophilin能促进脂质蓄积和细胞内脂滴的形成,在泡沫细胞的形成中起重要作用,是动脉粥样硬化脂质蓄积的一个标记物.Adipophilin基因敲除小鼠能预防高脂饮食诱导的脂肪肝产生,且在脂肪组织分化过程中也起着一定的作用.本文概述了adipophilin在细胞内脂质代谢中的作用.     

Toll-like receptor 3 ablation prevented high-fat diet-induced obesity and metabolic disorder

Inflammation in insulin-sensitive tissues (e.g., liver, visceral adipose tissue [VAT]) plays a major role in obesity and insulin resistance. Recruitment of innate immune cells drives the dysregulation of glucose and lipid metabolism. We aimed to seek the role of Toll like receptor 3 (TLR3), a pattern recognition receptor involved in innate immunity, obesity and the metabolic disorder. TLR3 expression in liver and VAT from diet induced obese mice and in VAT from overweight women was examined. Body weight, glucose homeostasis and insulin sensitivity were evaluated in TLR3 wild-type and knockout (KO) mice on a chow diet (CD) or high-fat diet for 15 weeks. At euthanasia, blood was collected, and plasma biochemical parameters and adipokines were determined with commercial kits. Flow cytometry was used to measure macrophage infiltration and activation in VAT. Standard western blot, immunohistochemistry and quantative PCR were used to assess molecules in pathways about lipid and glucose metabolism, insulin and inflammation in tissues of liver and VAT. Utilizing human and animal samples, we found that expression of TLR3 was upregulated in the liver and VAT in obese mice as well as VAT in overweight women. TLR3-deficiency protected against high-fat diet induced obesity, glucose intolerance, insulin resistance and lipid accumulation. Lipolysis was enhanced in VAT and hepatic lipogenesis was inhibited in TLR3 KO animals. Macrophages infiltration into adipose tissue was attenuated in TLR3 KO mice, accompanied with inhibition of NF-κB-dependent AMPK/Akt signaling pathway. These findings demonstrated that TLR3 ablation prevented obesity and metabolic disorders, thereby providing new mechanistic links between inflammation and obesity and associated metabolic abnormalities in lipid/glucose metabolism.     

Current approaches to unravel the mystery of dilated cardiomyopathy,a common cause of hereditary heart failure

As is well known, adipose tissue is an important site for lipid metabolism and insulin-responsive glucose uptake. The recent discovery of the endocrine function of adipose tissue and the association of obesity with chronic low-grade inflammation in adipose tissue has reinforced the concept of the central role of adipose tissue in mediating obesity-linked insulin resistance and metabolic dysregulation. The study of adipose cells has provided new insights into the mechanism underlying insulin resistance as well as the therapeutic strategies for diabetes. Numerous efforts have been made in identifying key molecular regulators of insulin action and metabolism, including the utilization of advanced proteomics technology. Various proteomic approaches have been applied to identify the adipose secretome, protein-expression profiling and post-translational modifications in adipose cells in the pathological state. In this review, we summarize the recent advances in the proteomics of adipose tissue, and discuss the identified proteins that potentially play important roles in insulin resistance and diabetes.     

Apolipoprotein A-IV regulates chylomicron metabolism-mechanism and function

Dietary fat is an important mediator of atherosclerosis and obesity. Despite its importance in mediating metabolic disease, there is still much unknown about dietary fat absorption in the intestine and especially the detailed biological roles of intestinal apolipoproteins involved in that process. We were specifically interested in determining the physiological role of the intestinal apolipoprotein A-IV (A-IV) using A-IV knockout (KO) mice. A-IV is stimulated by fat absorption in the intestine and is secreted on nascent chylomicrons into intestinal lymph. We found that A-IV KO mice had reduced plasma triglyceride (TG) and cholesterol levels and that this hypolipidemia persisted on a high-fat diet. A-IV KO did not cause abnormal intestinal lipid absorption, food intake, or adiposity. Additionally, A-IV KO did not cause abnormal liver TG and cholesterol metabolism, as assessed by measuring hepatic lipid content, lipogenic and cholesterol synthetic gene expression, and in vivo VLDL secretion. Instead, A-IV KO resulted in the secretion of larger chylomicrons from the intestine into the lymph, and those chylomicrons were cleared from the plasma more slowly than wild-type chylomicrons. These data suggest that A-IV has a previously unknown role in mediating the metabolism of chylomicrons, and therefore may be important in regulating plasma lipid metabolism.     

Subcutaneous fat accumulation shows a beneficial correlation with serum cholesterol in postmenopausal Japanese women

This study aimed to investigate whether accumulation of subcutaneous abdominal fat has a beneficial correlation with lipid metabolism in premenopausal and/or postmenopausal Japanese women. The study enrolled 146 premenopausal women, ranging in age from 19 to 54 years, and 82 postmeno-pausal women, ranging in age from 47 to 66 years. Fat distribution, including abdominal visceral fat area (VFA) and abdominal subcutaneous fat area (SFA), were measured in an outpatient clinic by magnetic resonance imaging. Homogeneity of the regression slopes for SFA to total cholesterol (P = 0.030), low-density lipoprotein cholesterol (P = 0.020), apolipoprotein B (apoB) (P = 0.001), and the ratio of apoB to apolipoprotein A-I (apoA-I) (P = 0.003) were not found between premenopausal and postmenopausal women, even after adjustment for both VFA and age. However, the regression slopes for VFA to all measured lipid parameters, as well as apolipoproteins, were homogeneous between the premenopausal and postmeno-pausal groups. Abdominal SFA in postmenopausal women correlated negatively with total cholesterol (P = 0.007), low-density lipoprotein cholesterol (P = 0.002), apoB (P < 0.001), and the ratio of apoB to apoA-I (P = 0.001), after adjustment for age and VFA, but this was not the case in premenopausal women. The mechanisms involved in the beneficial effects of subcutaneous fat accumulation in postmenopausal women remain obscure, but upregulated aromatase expression, derived from adipose tissue, may possibly improve lipid and apolipoprotein metabolism.     

内质网应激响应在脂肪组织中的代谢调节作用

在真核细胞中,内质网是蛋白合成、加工及质量监控的关键细胞器,也是Ca2+储存及脂质合成的重要场所.细胞通过未折叠蛋白响应(unfolded protein response,UPR)感应外界不同刺激引发的内质网应激,在维持细胞功能稳态中发挥至关重要的作用.在哺乳动物中,三个位于内质网的跨膜蛋白——肌醇依赖酶la(ino...     

Diabetes, lipids, and adipocyte secretagogues.

That obesity is associated with insulin resistance and type II diabetes mellitus is well accepted. Overloading of white adipose tissue beyond its storage capacity leads to lipid disorders in non-adipose tissues, namely skeletal and cardiac muscles, pancreas, and liver, effects that are often mediated through increased non-esterified fatty acid fluxes. This in turn leads to a tissue-specific disordered insulin response and increased lipid deposition and lipotoxicity, coupled to abnormal plasma metabolic and (or) lipoprotein profiles. Thus, the importance of functional adipocytes is crucial, as highlighted by the disorders seen in both "too much" (obesity) and "too little" (lipodystrophy) white adipose tissue. However, beyond its capacity for fat storage, white adipose tissue is now well recognised as an endocrine tissue producing multiple hormones whose plasma levels are altered in obese, insulin-resistant, and diabetic subjects. The consequence of these hormonal alterations with respect to both glucose and lipid metabolism in insulin target tissues is just beginning to be understood. The present review will focus on a number of these hormones: acylation-stimulating protein, leptin, adiponectin, tumour necrosis factor alpha, interleukin-6, and resistin, defining their changes induced in obesity and diabetes mellitus and highlighting their functional properties that may protect or worsen lipid metabolism.     

Contributions of domain structure and lipid interaction to the functionality of exchangeable human apolipoproteins

Exchangeable apolipoproteins function in lipid transport as structural components of lipoprotein particles, cofactors for enzymes and ligands for cell-surface receptors. Recent findings with apoA-I and apoE suggest that the tertiary structures of these two members of the human exchangeable apolipoprotein gene family are related. Characteristically, these proteins contain a series of proline-punctuated, 11- or 22-amino acid, amphipathic alpha-helical repeats that can adopt a helix bundle conformation in the lipid-free state. The amino- and carboxyl-terminal regions form separate domains with the latter being primarily responsible for lipid binding. Interaction with lipid induces changes in the conformation of the amino-terminal domain leading to alterations in function; for example, opening of the amino-terminal four-helix bundle in apolipoprotein E upon lipid binding is associated with enhanced receptor-binding activity. The concept of a two-domain structure for the larger exchangeable apolipoproteins is providing new molecular insights into how these apolipoproteins interact with lipids and other proteins, such as receptors. The ways in which structural changes induced by lipid interaction modulate the functionality of these apolipoproteins are reviewed.     

Adipose tissue proadipogenic redox changes in obesity

The role of inflammation and oxidative stress in the development of obesity and associated metabolic disorders is under debate. We investigated the redox metabolism in a non-diabetic obesity model, i.e. 11-week-old obese Zucker rats. Antioxidant enzyme activities, lipophilic antioxidant (alpha-tocopherol, coenzymes Q) and hydrophilic antioxidant (glutathione, vitamin C) contents and their redox state (% oxidized form), were studied in inguinal white fat and compared with blood and liver. The adipose tissues of obese animals showed a specific higher content of hydrophilic molecules in a lower redox state than those of lean animals, which were associated with lower lipophilic molecule content and lipid peroxidation. Conversely and as expected, glutathione content decreased and its redox state increased in adipose tissues of rats subjected to lipopolysaccharide-induced systemic oxidative stress. In these in vivo models, oxidative stress and obesity thus had opposite effects on adipose tissue redox state. Moreover, the increase in glutathione content and the decrease of its redox state by antioxidant treatment promoted in vitro the accumulation of triglycerides in preadipocytes. Taken together and contrary to the emergent view, our results suggest that obesity is associated with an intracellular reduced redox state that promotes on its own the development of a deleterious proadipogenic process.     

Intestinal absorption, blood transport and hepatic and muscle metabolism of fatty acids in preruminant and ruminant animals

Current research on lipid metabolism in ruminants aims to improve the growth and health of the animals and the muscle characteristics associated with meat quality. This review, therefore, focuses on fatty acid (FA) metabolism from absorption to partitioning between tissues and metabolic pathways. In young calves, which were given high-fat milk diets, lipid absorption is delayed because the coagulation of milk caseins results in the retention of dietary fat as an insoluble clot in the abomasum. After weaning, the calves were fed forage- and cereal-based diets containing low levels of long-chain fatty acids (LCFA) but leading to high levels of volatile fatty acid (VFA) production by the rumen microflora. Such differences in dietary FA affect: i) the lipid transport system via the production of lipoproteins by the intestine and the liver, and (ii) the subsequent metabolism of lipids and FA by tissues. In preruminant calves, high-fat feed stimulates the secretion of triacylglycerols (TG)-rich lipoproteins (chylomicrons, very-low density lipoproteins (VLDL)). Diets rich in polyunsaturated FA (PUFA) stimulate the production of chylomicrons by the intestine (at peak lipid absorption) and of high density lipoproteins by the liver, leading to high blood concentrations of cholesterol. High levels of non-esterified FA (NEFA) uptake by the liver in high-yielding dairy cows in early lactation leads to TG infiltration of the hepatocytes (fatty liver). This is due to the low chronic capacity of the liver to synthesise and secrete VLDL particles. This abnormality in hepatic FA metabolism involves defects in apolipoprotein B synthesis and low availability of apolipoproteins and lipids for VLDL packaging. Fatty liver in calves is also caused by milk containing either soybean oil (rich in n-6 PUFA), or coconut oil (rich in C12:0 and C14:0). The ability of muscle tissue to use FA as an energy source depends on its mitochondrial content and, hence, on many physiological factors. The uptake and partitioning of LCFA between oxidation and storage in muscle is regulated by the activity of key intracellular enzymes and binding proteins. One such protein, carnitine palmitoyltransferase I (CPT I) controls the transport of LCFA into mitochondria. Metabolites derived from LCFA inhibit glucose oxidation, decrease the activity of CPT I and decrease the efficiency of ATP production by mitochondria. Most research on tissue lipid metabolism in ruminants is focused on: i) the partitioning of FA oxidation between intracellular peroxisomes and mitochondria in the liver and in muscles; (ii) the regulation of lipid metabolism by leptin, a recently discovered hormone secreted by mature adipocytes; and iii) the effects of activation of the nuclear receptors (PPARs and RXR) by LCFA or by phytol metabolites derived from chlorophyll.     

PPARγ 基因与代谢综合征关系的研究进展

过氧化物酶体增殖物激活受体(PPARs)γ基因已被公认在调控脂肪细胞分化和多种代谢(糖、脂肪、能量代谢等)中起重要作用。它在脂肪、肌肉、肝脏等多种与胰岛素作用有关的组织中表达,并且具备激活后调控涉及葡萄糖的产生、转运、利用及脂肪代谢的调节等基因的表达。PPARγ基因在脂肪细胞分化、糖、脂代谢、动脉粥样硬化形成、炎性反应中起重要作用,从而与T2DM、胰岛素抵抗、肥胖症、心血管疾病和高血压等疾病的发病风险相关。本文综述了PPARγ基因的结构、功能及其多态性与代谢综合征关系的研究进展。