Lipasin, a novel nutritionally-regulated liver-enriched factor that regulates serum triglyceride levels

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.

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.