Role of LRP1 and ERK and cAMP Signaling Pathways in Lactoferrin-Induced Lipolysis in Mature Rat Adipocytes.

Keiko Ikoma-Seki,Hoyoku Nishino,Keikichi Sugiyama,Michiaki Murakoshi,Satoru Morishita,Hisashi Hirano,Tomoji Ono,Kanae Nakamura,Sally Martin

doi:10.1371/journal.pone.0141378

Abstract

Lactoferrin (LF) is a multifunctional glycoprotein present in milk. A clinical study showed that enteric-coated bovine LF tablets decrease visceral fat accumulation. Furthermore, animal studies revealed that ingested LF is partially delivered to mesenteric fat, and in vitro studies showed that LF promotes lipolysis in mature adipocytes. The aim of the present study was to determine the mechanism underlying the induction of lipolysis in mature adipocytes that is induced by LF. To address this question, we used proteomics techniques to analyze protein expression profiles. Mature adipocytes from primary cultures of rat mesenteric fat were collected at various times after exposure to LF. Proteomic analysis revealed that the expression levels of hormone-sensitive lipase (HSL), which catalyzes the rate-limiting step of lipolysis, were upregulated and that HSL was activated by protein kinase A within 15 min after the cells were treated with LF. We previously reported that LF increases the intracellular concentration of cyclic adenosine monophosphate (cAMP), suggesting that LF activates the cAMP signaling pathway. In this study, we show that the expression level and the activity of the components of the extracellular signal-regulated kinase (ERK) signaling pathway were upregulated. Moreover, LF increased the activity of the transcription factor cAMP response element binding protein (CREB), which acts downstream in the cAMP and ERK signaling pathways and regulates the expression levels of adenylyl cyclase and HSL. Moreover, silencing of the putative LF receptor low-density lipoprotein receptor-related protein 1 (LRP1) attenuated lipolysis in LF-treated adipocytes. These results suggest that LF promoted lipolysis in mature adipocytes by regulating the expression levels of proteins involved in lipolysis through controlling the activity of cAMP/ERK signaling pathways via LRP1.

Highlights

Metabolic syndrome comprises disorders that increase the risk of developing cardiovascular disease and other chronic ailments
Since we have previously demonstrated that the cyclic adenosine monophosphate (cAMP) and extracellular signal-regulated kinase (ERK) signaling pathways were activated by LF in mature adipocytes, we reasoned that cAMP response element binding protein (CREB) was synergistically activated by these two pathways
AC is stimulated by a G protein-coupled receptor (GPCR) similar to the βAR, and hormone-sensitive lipase (HSL) catalyzes a rate-limiting step in the pathway leading to lipolysis in adipocytes [33, 34]

Summary

Introduction

Metabolic syndrome comprises disorders that increase the risk of developing cardiovascular disease and other chronic ailments. Lack of exercise, and high levels of PLOS ONE | DOI:10.1371/journal.pone.0141378. Lactoferrin Induces Lipolysis by Activating ERK/cAMP Pathways via LRP1. Culture, Sports, Science and, Technology, Japan (ID: 11800122)). Lion Corporation had role in the study design, conduct of the study, data collection, data interpretation or preparation of the report, and the Establishment of Research Center for Clinical Proteomics of Post-Translational Modifications had a role in the study design, conduct of the study, data collection, data interpretation or preparation of the report in Proteomic analysis part

Objectives

Results

Conclusion