Biochemical and Biophysical Research Communications
Lipasin, a novel nutritionally-regulated liver-enriched factor that regulates serum triglyceride levels
Highlights
► The novel gene Gm6484 (named Lipasin) is nutritionally regulated. ► Human LIPASIN is liver specific, while the mouse one is enriched in liver and fat. ► Obesity increases liver Lipasin, whereas fasting reduces its expression in fat. ► Lipasin overexpression by adenoviruses increases serum triglyceride levels. ► A recombinant Lipasin inhibits the activity of lipoprotein lipase.
Introduction
The metabolic syndrome, a common metabolic disorder including glucose intolerance and dyslipidemia, has received significant attention, because the number of patients with this syndrome has increased dramatically in the past two decades [1], largely due to the global obesity epidemic [2], [3], [4]. Patients with metabolic syndrome are at high risk in developing atherosclerotic cardiovascular disease and diabetes, posing a major public health issue [5]. Of note, levels of blood lipids, such as triglycerides, are major contributors to cardiovascular diseases [6], [7]. There is an urgent need to develop novel therapeutic approaches to alleviate the burden from these diseases.
To identify genes involved in metabolism, the microarray technique has been routinely used to examine differential expression of genes from metabolic active organs, such as the liver, white adipose tissue (WAT) and brown adipose tissue (BAT), at different nutritional states, such as diet induced obesity and fasting [8], [9]. However, microarray technology has low sensitivity, and is limited to only known genes. In contrast, RNA-seq, a new sequencing based technology, is sensitive and identifies both known and unknown transcripts [10]. We therefore performed RNA-seq experiments on the liver and WAT in mice treated with a high-fat diet (HFD) or fasting.
Among the novel nutritionally regulated genes identified by the RNA-seq experiment (to publish elsewhere), we here focus on Gm6484 (Table 1), because of following reasons. (1) In humans, variations of C19ORF80, the human homologue of Gm6484, are linked to blood lipid levels by genome wide association studies [11]. (2) In mice, being among the mouse knockout library for secreted and transmembrane proteins, Gm6484 deletion largely reduced serum triglyceride levels [12]. We name the gene Lipasin (lipase inhibition). We here show that human LIPASIN is liver specific, while the mouse one is enriched in the liver and fat. Obesity increased Lipasin expression in the liver, while fasting reduced its expression in fat. Being evolutionarily conserved, LIPASIN is homologous to ANGPTL3’s N-terminal domain that regulates blood lipids, and to ANGPTL4’s N-terminal segment that mediates lipoprotein lipase (LPL) binding. Indeed, adenovirus-mediated overexpression of Lipasin increased serum triglycerides and a recombinant Lipasin inhibited LPL activity. Therefore, Lipasin is a novel nutritionally regulated liver-enriched factor that plays a role lipid metabolism.
Section snippets
Mice
Mice were housed at 22–24 °C with a 14-h light, 10-h dark cycle and provided with ad libitum water and a chow diet (6% calories from fat, 8664; Harlan Teklad, Indianapolis, IN) unless otherwise indicated. To examine nutritional stimulation induced gene expression, 10 4-week-old male C57B6 mice (Jackson Laboratory, Bar Habor, ME) were placed on either a chow diet or a high-fat, high-sucrose diet (58% kcal from fat, 26% kcal from sucrose, D-12331; Research Diets, New Brunswick, NJ) for 3 months.
Results and discussion
To comprehensively identify nutritionally regulated genes, we performed RNA-seq experiments on the liver and white adipose tissue, in mice treated with 3-month HFD or 24-h fasting, together with controls. Here, we focus on the analysis of the novel gene Lipasin, which was one of the identified genes that were sensitive to nutritional stimulation. We performed qPCR analysis to confirm the expression levels of Lipasin. Indeed, in obese mice induced by HFD, liver Lipasin was increased for more
Acknowledgments
The author thanks Fayi Yao for technical support and Dr. Abdul Abou-Samra for stimulating discussions. The present work was supported in part by a fund (176412) from Wayne State University to R.Z.
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