Liver-Specific Suppression of PLA2G6/iPLA₂β Improves Glucose and Lipid Metabolism in High-Fat Diet-Fed Mice

Shimizu, Kahori; Nishibata, Mana; Nagata, Katsuyuki; Hori, Sho; Michinaga, Shotaro; Kanehara, Miyuki; Hashimoto-Iwasaki, Miho; Sakurai, Fuminori; Shindou, Hideo; Tomita, Koji; Nishinaka, Toru; Mizuguchi, Hiroyuki

doi:https://doi.org/10.1096/fj.202504753RR

Liver-Specific Suppression of PLA2G6/iPLA₂β Improves Glucose and Lipid Metabolism in High-Fat Diet-Fed Mice

Shimizu, Kahori; Nishibata, Mana; Nagata, Katsuyuki et al.

FASEB Journal, 2026, 40(8), e71821

Number of Access:1,239（2026-11-12 09:48 Counts）

Identifier to cite or link to this item: https://hdl.handle.net/11094/104831

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Title	Liver-Specific Suppression of PLA2G6/iPLA₂β Improves Glucose and Lipid Metabolism in High-Fat Diet-Fed Mice
Creator	NRID 1000050737749 1000050737749 ORCID 0000-0003-1574-5526 0000-0003-1574-5526 researchmap permalink kahorishimizu kahorishimizu CreatorName Shimizu, Kahori
	CreatorName Nishibata, Mana
	CreatorName Nagata, Katsuyuki
	CreatorName Hori, Sho
	NRID 1000060624054 1000060624054 CreatorName Michinaga, Shotaro
	CreatorName Kanehara, Miyuki
	CreatorName Hashimoto-Iwasaki, Miho
	NRID 1000070370939 1000070370939 researchmap permalink read0165081 read0165081 Scopus Author ID 7003748169 7003748169 CreatorName Sakurai, Fuminori
	NRID 1000010401027 1000010401027 CreatorName Shindou, Hideo
	CreatorName Tomita, Koji
	NRID 1000090295642 1000090295642 CreatorName Nishinaka, Toru
	NRID 1000050311387 1000050311387 ORCID 0000-0003-0594-8178 0000-0003-0594-8178 researchmap permalink read0165079 read0165079 Scopus Author ID 57195381326 57195381326 CreatorName Mizuguchi, Hiroyuki
Subject	adenovirus vector
	diabetes mellitus
	metabolic disorders
	metabolic dysfunction-associated steatotic liver disease
	phospholipids
	PLA2G6
Description	Phospholipase A2 group VI (PLA2G6, also called iPLA2β) has been implicated in male fertility, neuronal disorders, and metabolic diseases. However, its therapeutic effects on metabolic disorders remain elusive. We investigated the effects of PLA2G6 suppression on glucose and lipid metabolism. Systemic inhibition of PLA2G6 in high-fat diet-fed mice reduced hepatic lipid droplet size without altering the levels of serum triglycerides and fasting blood glucose. Suppression of liver-specific 𝑃𝑙𝑎2𝑔6 utilizing the short-hairpin RNA knockdown technique using an adenovirus vector (Ad-shPLA2G6) altered phospholipid and fatty acid metabolites and suppressed hepatic lipid accumulation, serum triglyceride, fasting glucose, and insulin levels. Additionally, Ad-shPLA2G6 treatment downregulated lipid biosynthesis-related genes but upregulated peroxisomal fatty acid oxidation-related genes. These findings indicate that targeting hepatic 𝑃𝑙𝑎2𝑔6 modulates phospholipid and fatty acid metabolites and improves glucose and lipid metabolism, suggesting 𝑃𝑙𝑎2𝑔6 as a potential therapeutic target in metabolic disorders, including type 2 diabetes mellitus and metabolic dysfunction-associated steatotic liver disease.
Abstract	Phospholipase A2 group VI (PLA2G6, also called iPLA2β) has been implicated in male fertility, neuronal disorders, and metabolic diseases. However, its therapeutic effects on metabolic disorders remain elusive. We investigated the effects of PLA2G6 suppression on glucose and lipid metabolism. Systemic inhibition of PLA2G6 in high-fat diet-fed mice reduced hepatic lipid droplet size without altering the levels of serum triglycerides and fasting blood glucose. Suppression of liver-specific 𝑃𝑙𝑎2𝑔6 utilizing the short-hairpin RNA knockdown technique using an adenovirus vector (Ad-shPLA2G6) altered phospholipid and fatty acid metabolites and suppressed hepatic lipid accumulation, serum triglyceride, fasting glucose, and insulin levels. Additionally, Ad-shPLA2G6 treatment downregulated lipid biosynthesis-related genes but upregulated peroxisomal fatty acid oxidation-related genes. These findings indicate that targeting hepatic 𝑃𝑙𝑎2𝑔6 modulates phospholipid and fatty acid metabolites and improves glucose and lipid metabolism, suggesting 𝑃𝑙𝑎2𝑔6 as a potential therapeutic target in metabolic disorders, including type 2 diabetes mellitus and metabolic dysfunction-associated steatotic liver disease.
Publisher	John Wiley and Sons Inc
Source Title	FASEB Journal
Volume (Issue)	40(8)
Page	e71821
Date of Issued	2026-04-20
Language	English
Handle URL	https://hdl.handle.net/11094/104831
PISSN	08926638
eISSN	15306860
Relation.isIdenticalTo	DOI (Publisher Version) https://doi.org/10.1096/fj.202504753RR
Access Rights	open access
CopyRight	This article is licensed under a Creative Commons Attribution 4.0 International License.
oaire:version	Version of Record
Category	学術雑誌論文 Journal Article

Resource Type	journal article
Local Type	Journal Article
DCMI Type	Text
DCTERMS.bibliographicCitation	FASEB Journal. 2026, 40(8), p. e71821
DC.title	Liver-Specific Suppression of PLA2G6/iPLA₂β Improves Glucose and Lipid Metabolism in High-Fat Diet-Fed Mice
DC.creator	Shimizu, Kahori
	Nishibata, Mana
	Nagata, Katsuyuki
	Hori, Sho
	Michinaga, Shotaro
	Kanehara, Miyuki
	Hashimoto-Iwasaki, Miho
	Sakurai, Fuminori
	Shindou, Hideo
	Tomita, Koji
	Nishinaka, Toru
	Mizuguchi, Hiroyuki
DC.publisher	John Wiley and Sons Inc
DC.language' scheme='DCTERMS.RFC1766	English
DC.type' scheme='DCTERMS.DCMIType	Text
DCTERMS.issued' scheme='DCTERMS.W3CDTF	2026-04-20
DC.identifier	https://doi.org/10.1096/fj.202504753RR
DC.subject	adenovirus vector
	diabetes mellitus
	metabolic disorders
	metabolic dysfunction-associated steatotic liver disease
	phospholipids
	PLA2G6
DC.description	Phospholipase A2 group VI (PLA2G6, also called iPLA2β) has been implicated in male fertility, neuronal disorders, and metabolic diseases. However, its therapeutic effects on metabolic disorders remain elusive. We investigated the effects of PLA2G6 suppression on glucose and lipid metabolism. Systemic inhibition of PLA2G6 in high-fat diet-fed mice reduced hepatic lipid droplet size without altering the levels of serum triglycerides and fasting blood glucose. Suppression of liver-specific 𝑃𝑙𝑎2𝑔6 utilizing the short-hairpin RNA knockdown technique using an adenovirus vector (Ad-shPLA2G6) altered phospholipid and fatty acid metabolites and suppressed hepatic lipid accumulation, serum triglyceride, fasting glucose, and insulin levels. Additionally, Ad-shPLA2G6 treatment downregulated lipid biosynthesis-related genes but upregulated peroxisomal fatty acid oxidation-related genes. These findings indicate that targeting hepatic 𝑃𝑙𝑎2𝑔6 modulates phospholipid and fatty acid metabolites and improves glucose and lipid metabolism, suggesting 𝑃𝑙𝑎2𝑔6 as a potential therapeutic target in metabolic disorders, including type 2 diabetes mellitus and metabolic dysfunction-associated steatotic liver disease.
DCTERMS.abstract	Phospholipase A2 group VI (PLA2G6, also called iPLA2β) has been implicated in male fertility, neuronal disorders, and metabolic diseases. However, its therapeutic effects on metabolic disorders remain elusive. We investigated the effects of PLA2G6 suppression on glucose and lipid metabolism. Systemic inhibition of PLA2G6 in high-fat diet-fed mice reduced hepatic lipid droplet size without altering the levels of serum triglycerides and fasting blood glucose. Suppression of liver-specific 𝑃𝑙𝑎2𝑔6 utilizing the short-hairpin RNA knockdown technique using an adenovirus vector (Ad-shPLA2G6) altered phospholipid and fatty acid metabolites and suppressed hepatic lipid accumulation, serum triglyceride, fasting glucose, and insulin levels. Additionally, Ad-shPLA2G6 treatment downregulated lipid biosynthesis-related genes but upregulated peroxisomal fatty acid oxidation-related genes. These findings indicate that targeting hepatic 𝑃𝑙𝑎2𝑔6 modulates phospholipid and fatty acid metabolites and improves glucose and lipid metabolism, suggesting 𝑃𝑙𝑎2𝑔6 as a potential therapeutic target in metabolic disorders, including type 2 diabetes mellitus and metabolic dysfunction-associated steatotic liver disease.
DC.rights	This article is licensed under a Creative Commons Attribution 4.0 International License.
DC.format	104831
citation_title	Liver-Specific Suppression of PLA2G6/iPLA₂β Improves Glucose and Lipid Metabolism in High-Fat Diet-Fed Mice
citation_author	Shimizu, Kahori
	Nishibata, Mana
	Nagata, Katsuyuki
	Hori, Sho
	Michinaga, Shotaro
	Kanehara, Miyuki
	Hashimoto-Iwasaki, Miho
	Sakurai, Fuminori
	Shindou, Hideo
	Tomita, Koji
	Nishinaka, Toru
	Mizuguchi, Hiroyuki
citation_publisher	John Wiley and Sons Inc
citation_language	English
citation_date	2026-04-20
citation_journal_title	FASEB Journal
citation_volume	40
citation_issue	8
citation_firstpage	e71821
citation_doi	https://doi.org/10.1096/fj.202504753RR
citation_public_url	https://hdl.handle.net/11094/104831

Liver-Specific Suppression of PLA2G6/iPLA₂β Improves Glucose and Lipid Metabolism in High-Fat Diet-Fed Mice

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