Search

Copyright of Journal of Modern Laboratory Medicine is the property of Journal of Modern Laboratory Medicine Editorial Department and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Background Lipasin is a liver-derived secretory protein; i.e. associated with type 2 diabetes mellitus, obesity, and metabolic syndrome. Objective The current research assessed the effect of resistance training on atherogenic and metabolic status and lipasin levels in obese rats. Methods In this experimental study, 20 obese rats (8 weeks old, Mean±SD weight: 361±32 g) and 10 normal-weight rats (8 weeks old, Mean±SD weight: 248±13 g) randomly divided into three groups: obese control, obese trained, and control. The obese trained group received an 8-week exercise program for 3 days/week on a specific ladder with a carrying load of 30% of body weight, attached to their tails. The weight of the load was gradually increased during the training sessions, reaching 200% of the body weight of rats in the final week. There were three sets of 5 repetitions with a 3-min rest between each set of exercise sessions and 1 minute between repetitions. Forty-eight hours after the last training session, the blood samples were obtained and analyzed for metabolic status. The collected data were analyzed using analysis of variance (ANOVA), and statistical significance was set at P

Betatrophin, also known as TD26/RIFL/lipasin/ANGPTL8/C19orf80, is a novel protein predominantly expressed in human liver. To date, several betatrophin orthologs have been identified in mammals. Increasing evidence has revealed an association between betatrophin expression and serum lipid profiles, particularly in patients with obesity or diabetes. Stimulators of betatrophin, such as insulin, thyroid hormone, irisin and caloric intake, are usually relevant to energy expenditure or thermogenesis. In murine models, serum triglyceride levels as well as pancreatic cell proliferation are potently enhanced by betatrophin. Intriguingly, conflicting phenomena have also been reported that betatrophin suppresses hepatic triglyceride levels, suggesting that betatrophin function is mediated by complex regulatory processes. However, its precise physiological role remains unclear at present. In this review, we have summarized the current findings on betatrophin and their implications.

Lipasin, the product of the angiopoietin-like 8 (angptl8) gene, is known as a critical regulator of plasma lipid metabolism. However, its immune function in vertebrates is currently poorly understood. By 5'/3′-rapid amplification of cDNA ends (RACE), we established the structural identity of Nile tilapia (Oreochromis niloticus) angptl8. The transcripts of tilapia angptl8 were widely expressed in various tissues, with the highest levels in the liver. Following lipopolysaccharide in vivo challenges, time-dependent angptl8 gene expression was observed in the head kidney and liver. On the basis of the sequence obtained, we produced recombinant lipasin that inhibited lipoprotein lipase activity. Treatment of head kidney leukocytes with lipasin stimulated tumor necrosis factor-α (TNF-α) secretion and gene expression. In addition, lipasin-induced TNF-α secretion could be prevented by inhibiting the nuclear factor-kappa B (NF-κB) signaling pathway. Furthermore, lipasin enhanced the phosphorylation and degradation of IκBα and promoted translocation of the p65 subunit of NF-κB to the nucleus. Collectively, the current findings suggested that lipasin was involved in the immune response of Nile tilapia and stimulated TNF-α secretion by activating the NF-κB pathway in tilapia head kidney leukocytes. • Cloning of tilapia angptl8 and examination of its tissue expression patterns. • The LPS challenge induced the temporal expression of angptl8. • Synthesis of recombinant lipasin and validation of its biological activity. • Lipasin elevated TNF-α secretion and gene expression in head kidney leukocytes. • Lipasin stimulated TNF-α secretion by activating the NF-κB pathway. [ABSTRACT FROM AUTHOR]

Lipoprotein lipase (LPL) is a rate-limiting enzyme for hydrolysing circulating triglycerides (TG) into free fatty acids that are taken up by peripheral tissues. Postprandial LPL activity rises in white adipose tissue (WAT), but declines in the heart and skeletal muscle, thereby directing circulating TG to WAT for storage; the reverse is true during fasting. However, the mechanism for the tissue-specific regulation of LPL activity during the fed–fast cycle has been elusive. Recent identification of lipasin/angiopoietin-like 8 (Angptl8), a feeding-induced hepatokine, together with Angptl3 and Angptl4, provides intriguing, yet puzzling, insights, because all the three Angptl members are LPL inhibitors, and the deficiency (overexpression) of any one causes hypotriglyceridaemia (hypertriglyceridaemia). Then, why does nature need all of the three? Our recent data that Angptl8 negatively regulates LPL activity specifically in cardiac and skeletal muscles suggest an Angptl3-4-8 model: feeding induces Angptl8, activating the Angptl8–Angptl3 pathway, which inhibits LPL in cardiac and skeletal muscles, thereby making circulating TG available for uptake by WAT, in which LPL activity is elevated owing to diminished Angptl4; the reverse is true during fasting, which suppresses Angptl8 but induces Angptl4, thereby directing TG to muscles. The model suggests a general framework for how TG trafficking is regulated.

We previously identified a locus linked to total cholesterol (TC) concentration in Pima Indians on chromosome 19p. To characterize this locus, we genotyped > 2000 SNPs in 1838 Pimas and assessed association with log(TC). We observed evidence for association with log(TC) with rs2278426 (3.5% decrease/copy of the T allele; P = 5.045 × 10 − 6 ) in the ANGPTL8 (angiopoietin-like 8) gene. We replicated this association in 2413 participants of the San Antonio Mexican American Family Study (SAMAFS: 2.0% decrease per copy of the T allele; P = 0.005842). In a meta-analysis of the combined data, we found the strongest estimated effect with rs2278426 ( P = 2.563 × 10 − 7 ). The variant T allele at rs2278426 predicts an Arg59Trp substitution and has previously been associated with LDL-C and HDL-C. In Pimas and SAMAFS participants, the T allele of rs2278426 was associated with reduced HDL-C levels ( P = 0.000741 and 0.00002, respectively), and the combined estimated effect for the two cohorts was − 3.8% ( P = 8.526 × 10 − 8 ). ANGPTL8 transcript and protein levels increased in response to both glucose and insulin. The variant allele was associated with increased levels of cleaved ANGPTL3. We conclude that individuals with the variant allele may have lower TC and HDL-C levels due to increased activation of ANGPTL3 by ANGPTL8. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: The identification of novel targets that stimulate endogenous regeneration of beta cells would represent a significant advance in the treatment of patients with diabetes. The betatrophin hypothesis suggests that increased expression of angiopoietin-like protein 8 (ANGPTL8) induces dramatic and specific beta cell proliferation and subsequent beta cell mass expansion with improved glucose tolerance. In light of recent controversy, we further investigated the effects of ANGPTL8 overexpression on beta cell proliferation. Methods: We performed hydrodynamic tail vein injections of green fluorescent protein (GFP) or Angptl8 (also known as Gm6484) DNA in multiple cohorts of mice of different ages. We employed state-of-the-art methods to comprehensively quantify beta cell mass and proliferation, controlling for mouse age, genetic strain, source of DNA injected, Angptl8 gene expression and proliferation markers. Results: In two young and two aged cohorts of B6.129 mice, no substantial change in beta cell replication, mass or glucose homeostasis was observed following ANGPTL8 overexpression. Even in mice with extremely elevated Angptl8 expression (26-fold increase), beta cell replication was not significantly altered. Finally, we considered mice on the ICR background exactly as studied by Melton and colleagues, and still no beta cell mitogenic effect was detected following ANGPTL8 overexpression. Conclusion/interpretation: ANGPTL8 does not stimulate beta cell replication in young or old mice. [ABSTRACT FROM AUTHOR]

Metabolic syndrome includes glucose intolerance and dyslipidemia, both of which are strong risk factors for developing diabetes and atherosclerotic cardiovascular diseases. Recently, multiple groups independently studied a previously uncharacterized gene, officially named C19orf80 (human) and Gm6484 (mouse), but more commonly known as RIFL, Angptl8, betatrophin and lipasin. Both exciting and conflicting results have been obtained, and significant controversy is ongoing. Accumulating evidence from genome wide association studies and mouse genetic studies convincingly shows that lipasin is involved in lipid regulation. However, the mechanism of action, the identity of transcription factors mediating its nutritional regulation, circulating levels, and relationship among lipasin, Angptl3 and Angptl4, remain elusive. Betatrophin represents a promising drug target for replenishing β- cell mass, but current results have not been conclusive regarding its potency and specificity. Here, we summarize the consensus and controversy regarding functions of lipasin/betatrophin based on currently available evidence. [ABSTRACT FROM AUTHOR]

Abstract: Patients with metabolic syndrome are at high risk for developing atherosclerotic cardiovascular diseases and diabetes. In addition to total cholesterol, LDL-C and HDL-C, elevated plasma triglycerides (TG) are increasingly recognized as an independent risk factor for cardiovascular diseases. Recently 3 groups independently reported the identification and characterization of a novel blood lipid regulator, Lipasin/RIFL/ANGPTL8, which here is referred to as Lipasin for its lipoprotein lipase inhibition effect and for being a circulating factor denoted by ‘in’. Being highly enriched in the liver, Lipasin is a hepatocyte-derived circulating factor that regulates plasma TG levels. Lipasin is nutritionally regulated, as its mRNA levels in liver and fat as well as its protein level in serum are reduced by fasting. Mice deficient for Lipasin have lower serum TG levels; conversely, its adenovirus-mediated overexpression increases serum TG levels, in part, through promoting ANGPTL3 cleavage, releasing its N-terminal domain that inhibits lipoprotein lipase. Lipasin sequence variations are associated with LDL-C and HDL-C concentrations in humans. Being lipogenic, Lipasin is highly induced during adipogenesis. Levels of Lipasin and ANGPTL4 show opposite changes in response to fasting or cold environment. Lipasin, a novel but atypical ANGPTL family member, is emerging as a critical lipid regulator and a potential drug target. [Copyright &y& Elsevier]

Abstract: Hyperlipidemia is a major contributor to cardiovascular diseases. Members of the angiopoietin-like protein family (ANGPTLs) are important determinants of blood lipid levels. Lipasin, a newly identified gene that regulates serum triglycerides, is homologous to ANGPTL3’s N-terminal domain, which is sufficient and necessary for blood lipid regulation. Brown fat is critical in mediating energy homeostasis. Thermogenesis is the primary function of brown fat, in which Lipasin and some ANGPTLs are abundant; it is unknown, however, whether these genes are thermoregulated. We therefore comprehensively examined the thermoregulation of Lipasin and ANGPTLs in brown fat. Here we show that Lipasin is a novel but atypical member of the ANGPTL family because it is within the same branch as ANGPTL3 and 4 by phylogenetic analysis. The mRNA levels of Lipasin are dramatically increased in the cold environment (4°C for 4h) whereas those of ANGPTL4 and ANGPTL2 are suppressed. Fasting dramatically suppresses Lipasin but increases ANGPTL4. High-fat diet treatment increases Lipasin, but reduces ANGPTL2. The distinct transcriptional regulations of Lipasin, ANGPTL2 and ANGPTL4 in brown fat in response to cold exposure and nutritional stimulation suggest distinct physiological roles for ANGPTL family members in mediating thermogenesis and energy homeostasis. [Copyright &y& Elsevier]

Abstract: The metabolic syndrome, a common disorder including glucose intolerance and dyslipidemia, poses a major public health issue. Patients with high blood lipids, such as triglycerides, are at high risk in developing atherosclerotic cardiovascular diseases. To identify genes involved in metabolism, we performed RNA-seq experiments on the liver and fat in mice treated with a high-fat diet or fasting, and identified Gm6484 (named Lipasin) as a novel nutritionally regulated gene. Human LIPASIN is liver specific, while the mouse one is enriched in the liver and fat, including both brown and white adipose tissues. Obesity increases liver Lipasin, whereas fasting reduces its expression in fat. ANGPTL3 (Angiopoietin-like 3) and ANGPTL4 are critical regulators of blood lipids. LIPASIN shares homology with ANGPTL3’s N-terminal domain that is needed for lipid regulation, and with ANGPTL4’s N-terminal segment that mediates lipoprotein lipase (LPL) binding. Lipasin overexpression by adenoviruses in mice increases serum triglyceride levels, and a recombinant Lipasin inhibits LPL activity. Therefore, a potential mechanism for Lipasin-mediated triglyceride elevation is through reduced triglyceride clearance by LPL inhibition. Lipasin is thus a novel nutritionally-regulated liver-enriched factor that plays a role in lipid metabolism. [Copyright &y& Elsevier]

The present study recruited 74 participants with type 2 diabetes, among which 23 had retinopathy. Those with retinopathy had a longer duration of diabetes and higher levels of lipasin compared with those without retinopathy. Logistic regression revealed that lipasin was independently and significantly associated with retinopathy even after adjustments for confounders. [ABSTRACT FROM AUTHOR]

Betatrophin is a protein which is produced by the liver and by adipose tissue. There are no clear data about serum betatrophin's cardiovascular role and it is unknown, whether betatrophin is associated with the risk of cardiovascular death. This article provides additional data on the association of betatrophin with its power to predict cardiovascular death in coronary patients. In addition, this data article demonstrates the performance of betatrophin as a biomarker using c-statistics. Analyzed data was derived from 553 coronary patients. Betatrophin was measured in serum samples and cardiovascular deaths were recorded for a median of 7.1 years. This data article is related to a research article titled "High betatrophin in coronary patients protects from cardiovascular events" [1]., (© 2019 The Author(s).)

Betatrophin is a newly identified circulating adipokine playing a role in the regulation of glucose homeostasis and lipid metabolism. But its role in metabolic syndrome (MetS) remains unknown. Therefore, we aimed to compare the circulating betatrophin concentrations between patients with MetS and healthy controls. We recruited 47 patients with MetS and 47 age and sex matched healthy controls. Anthropometric and biochemical measurements were performed, and serum betatrophin levels were detected by ELISA. Full-length betatrophin levels in patients with MetS were significantly higher than those in controls (694.84 ± 365.51 pg/ml versus 356.64 ± 287.92 pg/ml; P <0.001). While no significant difference of total betatrophin levels was found between the two groups (1.20 ± 0.79 ng/ml versus 1.31 ± 1.08 ng/ml; P = 0.524). Full-length betatrophin level was positively correlated with fasting plasma glucose (FPG) (r = 0.357, P = 0.014) and 2-hour plasma glucose (2hPG) (r = 0.38, P <0.01). Binary logistic regression models indicated that subjects in the tertile of the highest full-length betatrophin level experienced higher odds of having MetS (OR, 8.6; 95% CI 2.8-26.8; P <0.001). Our study showed that full-length betatrophin concentrations were increased in drug-naïve MetS patients.

Lipoprotein lipase (LPL) is a rate-limiting enzyme for hydrolysing circulating triglycerides (TG) into free fatty acids that are taken up by peripheral tissues. Postprandial LPL activity rises in white adipose tissue (WAT), but declines in the heart and skeletal muscle, thereby directing circulating TG to WAT for storage; the reverse is true during fasting. However, the mechanism for the tissue-specific regulation of LPL activity during the fed-fast cycle has been elusive. Recent identification of lipasin/angiopoietin-like 8 (Angptl8), a feeding-induced hepatokine, together with Angptl3 and Angptl4, provides intriguing, yet puzzling, insights, because all the three Angptl members are LPL inhibitors, and the deficiency (overexpression) of any one causes hypotriglyceridaemia (hypertriglyceridaemia). Then, why does nature need all of the three? Our recent data that Angptl8 negatively regulates LPL activity specifically in cardiac and skeletal muscles suggest an Angptl3-4-8 model: feeding induces Angptl8, activating the Angptl8-Angptl3 pathway, which inhibits LPL in cardiac and skeletal muscles, thereby making circulating TG available for uptake by WAT, in which LPL activity is elevated owing to diminished Angptl4; the reverse is true during fasting, which suppresses Angptl8 but induces Angptl4, thereby directing TG to muscles. The model suggests a general framework for how TG trafficking is regulated., (© 2016 The Authors.)