2014 Vol. 28, No. 3
2014, 28(3): 155-156. doi: 10.7555/JBR.28.20130181
2014, 28(3): 157-168. doi: 10.7555/JBR.28.20140012
Obesity and the metabolic syndrome and their associated morbidities are major public health issues, whose prevalence will continue to increase in the foreseeable future. Aberrant signaling by the receptors for leptin and insulin plays a pivotal role in development of the metabolic syndrome. More complete molecular-level understanding of how both of these key signaling pathways are regulated is essential for full characterization of obesity, the metabolic syndrome, and type II diabetes, and for developing novel treatments for these diseases. Phosphorylation of proteins on tyrosine residues plays a key role in mediating the effects of leptin and insulin on their target cells. Here, we discuss the molecular methods by which protein tyrosine phosphatases, which are key physiological regulators of protein phosphorylation in vivo, affect signaling by the leptin and insulin receptors in their major target tissues.
2014, 28(3): 169-177. doi: 10.7555/JBR.28.20140029
Abnormal intracellular accumulation or transport of lipids contributes greatly to the pathogenesis of human diseases. In the liver, excess accumulation of triacylglycerol (TG) leads to fatty liver disease encompassing steatosis, steatohepatitis and fibrosis. This places individuals at risk of developing cirrhosis, hepatocellular carcinoma or hepatic decompensation and also contributes to the emergence of insulin resistance and dyslipidemias affecting many other organs. Excessive accumulation of TG in adipose tissue contributes to insulin resistance as well as to the release of cytokines attracting leucocytes leading to a pro-inflammatory state. Pathological accumulation of cholesteryl ester (CE) in macrophages in the arterial wall is the progenitor of atherosclerotic plaques and heart disease. Overconsumption of dietary fat, cholesterol and carbohydrates explains why these diseases are on the increase yet offers few clues for how to prevent or treat individuals. Dietary regimes have proven futile and barring surgery, no realistic alternatives are at hand as effective drugs are few and not without side effects. Overweight and obesity-related diseases are no longer restricted to the developed world and as such, constitute a global problem. Development of new drugs and treatment strategies are a priority yet requires as a first step, elucidation of the molecular pathophysiology underlying each associated disease state. The lipid droplet (LD), an up to now overlooked intracellular organelle, appears at the heart of each pathophysiology linking key regulatory and metabolic processes as well as constituting the site of storage of both TGs and CEs. As the molecular machinery and mechanisms of LDs of each cell type are being elucidated, regulatory proteins used to control various cellular processes are emerging. Of these and the subject of this review, small GTPases belonging to the Rab protein family appear as important molecular switches used in the regulation of the intracellular trafficking and storage of lipids.
Apolipoprotein B (apoB) is the main protein component of very low density lipoprotein (VLDL) and is necessary for the assembly and secretion of these triglyceride (TG)-rich particles. Following release from the liver, VLDL is converted to low density lipoprotein (LDL) in the plasma and increased production of VLDL can therefore play a detrimental role in cardiovascular disease. Increasing evidence has helped to establish VLDL assembly as a target for the treatment of dyslipidemias. Multiple factors are involved in the folding of the apoB protein and the formation of a secretion-competent VLDL particle. Failed VLDL assembly can initiate quality control mechanisms in the hepatocyte that target apoB for degradation. ApoB is a substrate for endoplasmic reticulum associated degradation (ERAD) by the ubiquitin proteasome system and for autophagy. Efficient targeting and disposal of apoB is a regulated process that modulates VLDL secretion and partitioning of TG. Emerging evidence suggests that significant overlap exists between these degradative pathways. For example, the insulin-mediated targeting of apoB to autophagy and postprandial activation of the unfolded protein response (UPR) may employ the same cellular machinery and regulatory cues. Changes in the quality control mechanisms for apoB impact hepatic physiology and pathology states, including insulin resistance and fatty liver. Insulin signaling, lipid metabolism and the hepatic UPR may impact VLDL production, particularly during the postprandial state. In this review we summarize our current understanding of VLDL assembly, apoB degradation, quality control mechanisms and the role of these processes in liver physiology and in pathologic states.
Certain pseudogenes may regulate their protein-coding cousins by competing for miRNAs and play an active biological role in cancer. However, few studies have focused on the association of genetic variations in pseudogenes with cancer prognosis. We selected six potentially functional single nucleotide polymorphisms (SNPs) in cancerrelated pseudogenes, and performed a case-only study to assess the association between those SNPs and the prognosis of hepatocellular carcinoma (HCC) in 331 HBV-positive HCC patients without surgical treatment. Log-rank test and Cox proportional hazard models were used for survival analysis. We found that the A allele of rs9909601 in E2F3P1 was significantly associated with a better prognosis compared with the G allele [adjusted hazard ratio (HR) 5 0.69, 95% confidence interval (CI) 5 0.56-0.86, P 5 0.001]. Additionally, this protective effect was more predominant for patients without chemotherapy and transcatheter hepatic arterial chemoembolization (TACE) treatment. Interestingly, we also detected a statistically significant multiplicative interaction between genotypes of rs9909601 and chemotherapy or TACE status on HCC survival (P for multiplicative interaction , 0.001). These findings indicate that rs9909601 in the pseudogene E2F3P1 may be a genetic marker for HCC prognosis in Chinese.
This study aimed to examine whether expression of human hepatic lipase (hHL) exerted an intracellular effect on hepatic production of apolipoprotein (apo) A-I. The levels of secreted and cell-associated apoA-I were contrasted between primary hepatocytes isolated from Lipc-null and C57BL/6 mice, and between Lipc-null hepatocytes transfected with either hHL-encoding or control adenovirus. An HSPG-binding deficient hHL protein (hHLmt) was used to determine the impact of cell surface binding on HL action. Accumulation of apoA-I in conditioned media of primary hepatocytes isolated from Lipc-null mice was increased as compared to that from C57BL/6 mice. Metabolic labeling experiments showed that secretion of 35S-apoA-I from Lipc-null cells was significantly higher than that from C57BL/6 cells. Expression of hHL in Lipc-null hepatocytes, through adenovirus-mediated gene transfer, resulted in decreased synthesis and secretion of 35S-apoA-I, but not 35S-apoE, as compared with cells transfected with control adenovirus. Expression of HSPG-binding deficient hHLmt in Lipc-null cells also exerted an inhibitory effect on apoA-I production, even though hHLmt displayed impaired exit from the endoplasmic reticulum as compared with hHL. Subcellular fractionation revealed that expression of hHL or hHLmt led to increased microsome-association of apoA-I relative to non-transfected control. Expression of hHL negatively impacts hepatic production of apoA-I.
Macrophage death in advanced atherosclerosis promotes plaque necrosis and destabilization. Autophagy func?tions in bulk degradation of cellular components, has been recognized recently as an important mechanism for cell survive under endoplasmic reticulum (ER) stress. We previously found that engagement of the class A scavenger receptor (SR-A) triggered JNK-dependent apoptosis in ER-stressed macrophages. However, the pro-apoptosis mechanisms mediated by SR-A are not fully understood. We therefore sought to see if SR-A mediated apoptosis was associated with the autophagy in macrophages. In this study, we showed that fucoidan inhibited microtubule-associated protein light chain 3-phospholipid conjugates (LC3-II) formation as well as the number of autophago?somes under ER stress. The inhibition of LC3-II formation was paralleled by activation of mTOR pathways, and inhibition of mTOR allowed LC3-II induction in macrophages treated with thapsigargin plus fucoidan. Further?more, apoptosis induced by fucoidan was prevented under ER stress by the inhibitor of mTOR treatment. We propose that fucoidan, a SR-A agonist, may contribute to macrophages apoptosis during ER stress by inhibition of autophagy.
Though obstructive sleep apnea hypopnea syndrome (OSAHS) and metabolic syndrome (MS) are correlated; the contributing factors for the occurrence of MS in Chinese snorers remain largely undefined. We aimed to investigate the associated pathogenesis of coexistence of OSAHS and MS in Chinese snorers. A total of 144 Chinese habitual snorers were divided into 3 groups, the control group (simple snorers) (n = 36), the mild OSAHS group (n = 52) and the moderate-to-severe OSAHS group (n = 56). The incidence of MS in the moderate-to-severe OSAHS group (26.8%) was significantly higher than that in the control group (8.3%), the mild OSAHS group (11.1%) and all the OSAHS patients (19.45%) (all P＜0.05). Homeostatic model assessment (HOMA) index and proinsulin (PI) were negatively correlated with nocturnal meanSpO2 and miniSpO2. Meanwhile, nocturnal SpO2 were negatively correlated with body mass index, waist and neck circumferences and diastolic blood pressure, but positively correlated with total cholesterol and high-density lipoprotein cholesterol. The study indicated that in Chinese snorers, moderate- to-severe OSAHS was closely associated with MS via nocturnal hypoxemia.
Computer-navigated pedicle screw insertion is applied to the thoracic and lumbar spine to attain high insertion accuracy and a low rate of screw-related complications. However, some in vivo and in vitro studies have shown that no advantages are gained with the use of navigation techniques compared to conventional techniques. Additionally, inconsistent conclusions have been drawn in various studies due to different population characteristics and methods used to assess the accuracy of screw placement. Moreover, it is not clear whether pedicle screw insertion with navigation techniques decreases the incidence of screw-related complications. Therefore, this study was sought to perform a meta-analysis of all available prospective evidence regarding pedicle screw insertion with or without navigation techniques in human thoracic and lumbar spine. We considered in vivo comparative studies that assessed the results of pedicle screw placement with or without navigation techniques. PubMed, Ovid MEDLINE and EMBASE databases were searched. Three published randomized controlled trials (RCTs) and nine retrospective comparative studies met the inclusion criteria. These studies included a total of 732 patients in whom 4,953 screws were inserted. In conclusion, accuracy of the position of grade I, II, III and IV screws and complication rate related to pedicle screw placement were significantly increased when navigation techniques were used in comparison to conventional techniques. Future research in this area should include RCTs with well-planned methodology to limit bias and report on validated, patient-based outcome measures.
Many surgeons practice prophylactic drainage after cholecystectomy without reliable evidence. This study was conducted to answer the question whether to drain or not to drain after cholecystectomy for acute calculous cholecystitis. A retrospective review of all patients who had cholecystectomy for acute cholecystitis in Aseer Central Hospital, Abha, Saudi Arabia, was conducted from April 2010 to April 2012. Data were extracted from hospital case files. Preoperative data included clinical presentation, routine investigations and liver function tests. Operative data included excessive adhesions, bleeding, bile leak, and drain insertion. Complicated cases such as pericholecystic collections, mucocele and empyema were also reported. Patients who needed therapeutic drainage were excluded. Postoperative data included hospital stay, volume of drained fluid, time of drain removal, and drain site problems. The study included 103 patients allocated into two groups; group A (n 5 38) for patients with operative drain insertion and group B (n 5 65) for patients without drain insertion. The number of patients with preoperative diagnosis of acute non-complicated cholecystitis was significantly greater in group B (80%) than group A (36.8%) (P , 0.001). Operative time was significantly longer in group A. All patients who were converted from laparoscopic to open cholecystectomy were in group A.Multivariate analysis revealed that hospital stay was significantly (P , 0.001) longer in patients with preoperative complications. There was no added benefit for prophylactic drain insertion after cholecystectomy for acute calculous cholecystitis in non-complicated or in complicated cases.