Liver-specific loss of lipin-1-mediated phosphatidic acid phosphatase activity does not mitigate intrahepatic TG accumulation in mice.
Lipin proteins (lipin 1, 2, and 3) regulate glycerolipid homeostasis by acting as phosphatidic acid phosphohydrolase (PAP) enzymes in the TG synthesis pathway and by regulating DNA-bound transcription factors to control gene transcription. Hepatic PAP activity could contribute to hepatic fat accumulation in response to physiological and pathophysiological stimuli. To examine the role of lipin 1 in regulating hepatic lipid metabolism, we generated mice that are deficient in lipin-1-encoded PAP activity in a liver-specific manner (Alb-Lpin1(-/-) mice). This allele of lipin 1 was still able to transcriptionally regulate the expression of its target genes encoding fatty acid oxidation enzymes, and the expression of these genes was not affected in Alb-Lpin1(-/-) mouse liver. Hepatic PAP activity was significantly reduced in mice with liver-specific lipin 1 deficiency. However, hepatocytes from Alb-Lpin1(-/-) mice had normal rates of TG synthesis, and steady-state hepatic TG levels were unaffected under fed and fasted conditions. Furthermore, Alb-Lpin1(-/-) mice were not protected from intrahepatic accumulation of diacylglycerol and TG after chronic feeding of a diet rich in fat and fructose. Collectively, these data demonstrate that marked deficits in hepatic PAP activity do not impair TG synthesis and accumulation under acute or chronic conditions of lipid overload.
Washington University School of Medicine, St. Louis, MO 63110.
George G
GG
Schweitzer
Washington University School of Medicine, St. Louis, MO 63110.
Zhouji
Z
Chen
Washington University School of Medicine, St. Louis, MO 63110.
Connie
C
Gan
Washington University School of Medicine, St. Louis, MO 63110.
Kyle S
KS
McCommis
Washington University School of Medicine, St. Louis, MO 63110.
Nisreen
N
Soufi
Department of Medical Genetics, University of Lausanne, 1005 Lausanne, Switzerland.
Roman
R
Chrast
Washington University School of Medicine, St. Louis, MO 63110.
Mayurranjan S
MS
Mitra
Washington University School of Medicine, St. Louis, MO 63110.
Kui
K
Yang
Washington University School of Medicine, St. Louis, MO 63110.
Richard W
RW
Gross
Washington University School of Medicine, St. Louis, MO 63110.
Brian N
BN
Finck
D000483:Alleles; D000818:Animals; D005215:Fasting; D005227:Fatty Acids / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D022781:Hepatocytes / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000201:enzymology* / Q000378:metabolism; D051379:Mice; D009687:Nuclear Proteins / Q000172:deficiency* / Q000235:genetics; D009928:Organ Specificity; D010084:Oxidation-Reduction; D010711:Phosphatidate Phosphatase / Q000172:deficiency* / Q000235:genetics; D014158:Transcription, Genetic; D014280:Triglycerides / Q000096:biosynthesis / Q000378:metabolism*
D005227:Fatty Acids; D009687:Nuclear Proteins; D014280:Triglycerides; C418978:Lpin1 protein, mouse; D010711:Phosphatidate Phosphatase
diacylglycerol; fatty acid metabolism; insulin signaling; lipid; phospholipids; triglyceride