Perilipin-5 is regulated by statins and controls triglyceride contents in the hepatocyte.
OBJECTIVE
Perilipin-5 (PLIN5) is a member of the perilipin family of lipid droplet (LD)-associated proteins. PLIN5 is expressed in oxidative tissues including the liver, and is critical during LD biogenesis. Studies showed that statins reduce hepatic triglyceride contents in some patients with non-alcoholic fatty liver disease and in rodent models of diet-induced hepatosteatosis. Whether statins alter triglyceride synthesis, storage, and/or utilization within the hepatocyte is unknown, though. Here we tested the hypothesis that statins alter the metabolism of LD in the hepatocyte during physiological conditions, such as fasting-induced steatosis.


METHODS
Mice were gavaged with saline or atorvastatin, and the expression of LD-associated genes was determined in fed and fasted animals. The accumulation of triglycerides and LD was studied in mouse or human primary hepatocytes in response to statins, and following knock-down of SREBP2 or PLIN5.


RESULTS
We show that statins decrease the levels of PLIN5, but not other LD-associated genes, in both mouse liver and mouse/human primary hepatocytes, which is paralleled by a significant reduction in both intracellular triglycerides and the number of LD. We identify an atypical negative sterol regulatory sequence in the proximal promoter of mouse/human PLIN5 that recruits the transcription factor SREBP2 and confers response to statins. Finally, we show that the statin-dependent reduction of hepatocyte triglyceride contents is mimicked by partial knock-down of PLIN5; conversely, ectopic overexpression of PLIN5 reverts the statin effect.


CONCLUSIONS
PLIN5 is a physiological regulator of triglyceride metabolism in the liver, and likely contributes to the pleiotropic effects of statins.
Edward A. Doisy Department of Biochemistry & Molecular Biology, and Center for Cardiovascular Research, Saint Louis University, Saint Louis, MO 63104, United States.
Cédric
C
Langhi
Edward A. Doisy Department of Biochemistry & Molecular Biology, and Center for Cardiovascular Research, Saint Louis University, Saint Louis, MO 63104, United States.
Tyler J
TJ
Marquart
Edward A. Doisy Department of Biochemistry & Molecular Biology, and Center for Cardiovascular Research, Saint Louis University, Saint Louis, MO 63104, United States.
Ryan M
RM
Allen
Edward A. Doisy Department of Biochemistry & Molecular Biology, and Center for Cardiovascular Research, Saint Louis University, Saint Louis, MO 63104, United States. Electronic address: abaldan1@slu.edu.
Angel
A
Baldán
D000818:Animals; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D047908:Intracellular Signaling Peptides and Proteins / Q000032:analysis / Q000502:physiology*; D066292:Lipid Droplets / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009124:Muscle Proteins / Q000032:analysis / Q000502:physiology*; D051782:Sterol Regulatory Element Binding Protein 2 / Q000502:physiology; D014280:Triglycerides / Q000378:metabolism*
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D009124:Muscle Proteins; C497391:Srebf2 protein, mouse; D051782:Sterol Regulatory Element Binding Protein 2; D014280:Triglycerides; C551268:lipid storage droplet protein 5, mouse
Fatty acid oxidation; Liver; PLIN5; Steatosis; Triglycerides