Cell Metab. 2014 Jul 1;20(1):119-32. doi: 10.1016/j.cmet.2014.05.002.

The Adipocyte-Inducible Secreted Phospholipases PLA2G5 and PLA2G2E Play Distinct Roles in Obesity

Sato H1, Taketomi Y1, Ushida A2, Isogai Y2, Kojima T3, Hirabayashi T3, Miki Y1, Yamamoto K3, Nishito Y4, Kobayashi T5, Ikeda K6, Taguchi R7, Hara S8, Ida S9, Miyamoto Y9, Watanabe M9, Baba H9, Miyata K10, Oike Y10, Gelb MH11, Murakami M12.

  • 1Lipid Metabolism Project, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo 156-8506, Japan; Department of Health Chemistry, Showa University, School of Pharmacy, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan.
  • 2Lipid Metabolism Project, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo 156-8506, Japan; Department of Biology, Faculty of Science, Ochanomizu University, 2-1-1 Otsuka, Bunkyo-ku, Tokyo 112-8610, Japan.
  • 3Lipid Metabolism Project, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo 156-8506, Japan.
  • 4Core Technology and Research Center, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo 156-8506, Japan.
  • 5Department of Biology, Faculty of Science, Ochanomizu University, 2-1-1 Otsuka, Bunkyo-ku, Tokyo 112-8610, Japan.
  • 6Institute for Advanced Biosciences, Keio University, 246-2 Mizukami, Kakuganji, Tsuruoka, Yamagata 997-0052, Japan.
  • 7Department of Biomedical Sciences, College of Life and Health Sciences, Chubu University, 1200 Matsumoto-cho, Kasugai-shi, Aichi 487-8501, Japan.
  • 8Department of Health Chemistry, Showa University, School of Pharmacy, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan.
  • 9Department of Gastroenterological Surgery, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto 860-8556, Japan.
  • 10Department of Molecular Genetics, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto 860-8556, Japan.
  • 11Departments of Chemistry and Biochemistry, University of Washington, Campus Box 351700, 36 Bagley Hall, Seattle, WA 98195, USA.
  • 12Lipid Metabolism Project, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo 156-8506, Japan; CREST, Japan Science and Technology Agency, 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan. Electronic address: murakami-mk@igakuken.or.jp.

 

ABSTRACT:

Metabolic disorders including obesity and insulin resistance have their basis in dysregulated lipid metabolism and low-grade inflammation. In a microarray search of unique lipase-related genes whose expressions are associated with obesity, we found that two secreted phospholipase A2s (sPLA2s), PLA2G5 and PLA2G2E, were robustly induced in adipocytes of obese mice. Analyses of Pla2g5–/– and Pla2g2e–/– mice revealed distinct and previously unrecognized roles of these sPLA2s in diet-induced obesity. PLA2G5 hydrolyzed phosphatidylcholine (PC) in fat-overladen low-density lipoprotein to release unsaturated fatty acids, which prevented palmitate-induced M1 macrophage polarization. As such, PLA2G5 tipped the immune balance toward an M2 state, thereby counteracting adipose tissue inflammation, insulin resistance, hyperlipidemia and obesiy. PLA2G2E altered minor lipoprotein phospholipids, phosphatidylserine (PS) and phosphatidylethanolamine (PE), and moderately facilitated lipid accumulation in adipose tissue and liver. Collectively, the identification of “metabolic sPLA2s” adds this gene family to a growing list of lipolytic enzymes that act as metabolic coordinators. Copyright © 2014 Elsevier Inc.

PMID: 24910243

 

SUPPLEMENT:

We performed gene profiling by microarray followed by quantitative RT-PCR of perigonadal white adipose tissue from C57BL/6 mice fed a high-fat diet in comparison with those maintained on a low-fat diet to identify particular lipase-related genes whose expression levels were altered by diets and whose functions in obesity are currently unknown. In this screening, we found that two sPLA2 isoforms (PLA2G5 and PLA2G2E) are robustly induced in adipocytes of obese mice (1). The induction of PLA2G2E depends on adipogenesis, whereas that of PLA2G5 requires adipogenesis plus endoplasmic reticulum (ER) stress. Because of this property, we refer to these two sPLA2s as “metabolic sPLA2s”.

Although sPLA2s have been implicated in inflammation, immunity, digestion and reproduction (2-4), their roles in metabolic diseases have remained obscure. The obesity-driven induction of PLA2G5 in hypertrophic adipocytes, along with its constitutive expression at relatively high levels in the heart and skeletal muscle which have a high demand for lipids as an energy source, suggests that one of the primary roles of this sPLA2 may be related to the regulation of energy metabolism. Notably, when fed a high-fat diet (HFD), Pla2g5-/- mice displayed hyperlipidemia with higher plasma levels of LDL, increased obesity and hepatic steatosis, and lower insulin sensitivity (Figure 1). Furthermore, adipose tissues in Pla2g5-/- mice showed greater infiltration of M1 macrophages and higher expression of pro-inflamamtory cytokines, indicating that PLA2G5 plays anti-obesity and anti-inflammatory roles in the context of metabolic disorders (1). Lipidomics revealed that PLA2G5 secreted from hypertrophic adipocytes preferentially hydrolyzed PC in fat-overladen LDL to release unsaturated fatty acids (e.g. oleate and linoleate). As such, the increased LDL lipid levels in Pla2g5-/- mice could impact on adipocyte hypertrophy and fatty liver. Furthermore, in accordance with the alterations in LDL phospholipids, levels of free oleate and linoleate were lower in adipose tissue of HFD-fed Pla2g5-/- mice than in WT mice. These PLA2G5-released unsaturated fatty acids dampened M1 macrophage polarization by saturated fatty acids (e.g. palmitate), probably through attenuating ER stress. Another intriguing feature of PLA2G5 is that it is a “Th2/M2-prone sPLA2”, allowing a shift in immune balance toward the Th2/M2 status. Apart from the crucial role of adipocyte- rather than macrophage-derived PLA2G5 in obesity, Pla2g5 expression in macrophages is markedly induced by the M2-skewing Th2 cytokines IL-4 and IL-13, and Pla2g5 ablation decreases Th2-mediated immune responses (1). Given the increased incidence of metabolic disorders resulting from genetic ablation of Th2 or M2 inducers (e.g. Il4, Il13, Il33, Stat6 or Pparg), the decreased whole-body Th2/M2 status resulting from Pla2g5 ablation may also contribute to exacerbation of obesity-associated inflammation. Moreover, PLA2G5 expression in human visceral adipose tissue inversely correlates with LDL levels (1), implying a human relevance for the metabolic role of PLA2G5.

Pla2g2e-/- mice are modestly protected from diet-induced obesity, hepatic steatosis and hyperlipidemia (Figure 2). In contrast to PLA2G5, which hydrolyzes PC in LDL to selectively release oleate and linoleate (see above), sPLA2-IIE preferentially hydrolyzes minor lipoprotein phospholipids, PS and PE, with no apparent fatty acid selectivity. As such, PLA2G2E alters the lipid composition of lipoproteins, thereby moderately affecting lipid accumulation in adipose tissue and liver (1). Although the molecular mechanism that links lipoprotein PS/PE hydrolysis with obesity still remains unclear, this study revealed for the first time the importance of these minor lipoprotein phospholipids in metabolic regulation.

Collectively, our results underscores the physiological relevance of lipoprotein hydrolysis by sPLA2s, highlights “metabolic sPLA2s” as integrated regulators of immune and metabolic responses, and brings about a paradigm shift toward a better understanding of the biological roles of this extracellular lipolytic enzyme family as a metabolic coordinator (Figure 3).

 

Acknowledgment

This work was supported by grants-in aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan and CREST from the Japan Science and Technology Agency.

References

1. Sato H, Taketomi Y, Ushida A, Isogai Y, Kojima T, Hirabayashi T, Miki Y, Yamamoto K, Nishito Y, Kobayashi T, Ikeda K, Taguchi R, Hara S, Ida S, Miyamoto Y, Watanabe M, Baba H, Miyata K, Oike Y, Gelb MH, Murakami M (2014) The Adipocyte-inducible secreted phospholipases PLA2G5 and PLA2G2E play distinct roles in obesity. Cell Metab 20:119-132
2. Taketomi Y, Ueno N, Kojima T, Sato H, Murase R, Yamamoto K, Tanaka S, Sakanaka M, Nakamura M, Nishito Y, Kawana M, Kambe N, Ikeda K, Taguchi R, Nakamizo S, Kabashima K, Gelb MH, Arita M, Yokomizo T, Nakamura M, Watanabe K, Hirai H, Nakamura M, Okayama Y, Ra C, Aritake K, Urade Y, Morimoto K, Sugimoto Y, Shimizu T, Narumiya S, Hara S, Murakami M (2013) Mast cell maturation is driven via a group III phospholipase A2-prostaglandin D2-DP1 receptor paracrine axis. Nat Immunol 14:554-563
3. Miki Y, Yamamoto K, Taketomi Y, Sato H, Shimo K, Kobayashi T, Ishikawa Y, Ishii T, Nakanishi H, Ikeda K, Taguchi R, Kabashima K, Arita M, Arai H, Lambeau G, Bollinger JM, Hara S, Gelb MH, Murakami M (2013) Lymphoid tissue phospholipase A2 group IID resolves contact hypersensitivity by driving antiinflammatory lipid mediators. J Exp Med 210:1217-1234
4. Sato H, Taketomi Y, Isogai Y, Miki Y, Yamamoto K, Masuda S, Hosono T, Arata S, Ishikawa Y, Ishii T, Kobayashi T, Nakanishi H, Ikeda K, Taguchi R, Hara S, Kudo I, Murakami M (2010) Group III secreted phospholipase A2 regulates epididymal sperm maturation and fertility in mice. J Clin Invest 120:1400-1414

 

Contact:

Makoto Murakami, PhD
Lipid Metabolism Project
Department of Advanced Science for Biomolecules
Tokyo Metropolitan Institute of Medical Science
2-1-6 Kamikitazawa, Setagaya
Tokyo 156-8506
Japan
murakami-mk@igakuken.or.jp

Fig-1 Fig 1. Pla2g5–/– mice display Increased diet-induced obesity, hepatic steatosis, and insulin resistance.

Fig-2Fig 2. Pla2g2e–/– mice are protected from diet-induced obesity and hepatic steatosis.

Fig-3Fig 3. Metabolic regulation by sPLA2s.

 

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