AGPAT2 (1-acyl-sn-glycerol-3-phosphate acyltransferase 2) converts lysophosphatidic acid (LPA) into phosphatidic acid (PA) and mutations of the AGPAT2 gene are responsible for the most common form of congenital generalized lipodystrophy (CGL) which leads to diabetes and steatohepatitis. The underlying mechanism by which AGPAT2 deficiency leads to these abnormalities has not been elucidated. We explored this question using an antisense oligonucleotide (ASO) to knock down expression of AGPAT2 in liver and white adipose tissue (WAT) of adult male SD rats. AGPAT2 ASO treatment induced lipodystrophic features in which adipose and hepatic inflammation were associated with increased LPA content in WAT (Control ASO=0.4 ± 0.1 nmol/g tissue; AGPAT2 ASO=0.8 ± 0.4, P<0.05) and liver (Control ASO=2.7 ± 0.4 nmol/g tissue; AGPAT2 ASO=4.2 ± 0.9, P<0.01) whereas PA content was unchanged. We hypothesized that increased LPA content may lead to inflammation in these tissues. We tested if either a controlled-release mitochondrial protonophore (CRMP) or an ASO against glycerol-3-phosphate acyltransferase, mitochondrial (GPAM) would reduce LPA content and inflammation in these tissues in AGPAT2 ASO treated rats. CRMP treatment (20 mg/[kg-day]) primarily prevented LPA accumulation in WAT (Control ASO=0.4 ± 0.1 nmol/g tissue; AGPAT2 ASO=0.9 ± 0.1; AGPAT2 ASO+CRMP=0.6 ± 0.1) (AGPAT2 ASO vs AGPAT2+CRMP P<0.05) and prevented WAT inflammation. In contrast GPAM ASO treatment primarily prevented hepatic LPA accumulation (Control ASO=3.6 ± 0.4 nmol/g tissue; AGPAT2 ASO=4.8 ± 0.2; AGPAT2+GPAM ASO=2.7 ± 0.4) (AGPAT2 ASO vs AGPAT2+GPAM ASO P<0.01) and prevented hepatic inflammation.

Conclusion: These results demonstrate a key role of LPA acid in mediating inflammation in liver and WAT in AGPAT2 deficient animals and identify novel therapeutic targets to treat CGL in patients with AGPAT2 deficiency.


I.Sakuma: None. R.C.Gaspar: None. P.Luukkonen: None. M.Kahn: None. S.Murray: Employee; Ionis Pharmaceuticals. V.Samuel: None. K.Petersen: Advisory Panel; Novo Nordisk, Research Support; Merck Sharp & Dohme Corp., Gilead Sciences, Inc. G.I.Shulman: Consultant; Novo Nordisk, DiCerna Pharmaceuticals, Inc., Bayer Consumer Care AG, Kriya Therapeutics, Arrowhead Pharmaceuticals, Inc., ESPERION Therapeutics, Inc., Other Relationship; AstraZeneca, Merck & Co., Inc., Janssen Research & Development, LLC, iMetabolic Biopharma Corporation, Maze Therapeutics, 89bio, Inc., Equator Therapeutics, Inc., Generian Pharmaceuticals, Fortress Biotech, Inc., OrsoBio, Aro Biotherapeutics Company, Stock/Shareholder; Levels Health, Inc.

Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at