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J Hepatol. 2014 Aug;61(2):358-65. doi: 10.1016/j.jhep.2014.04.009. Epub 2014 Apr 21.

Perilipin-5 is regulated by statins and controls triglyceride contents in the hepatocyte.

Author information

1
Edward A. Doisy Department of Biochemistry & Molecular Biology, and Center for Cardiovascular Research, Saint Louis University, Saint Louis, MO 63104, United States.
2
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.

Abstract

BACKGROUND & AIMS:

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.

KEYWORDS:

Fatty acid oxidation; Liver; PLIN5; Steatosis; Triglycerides

PMID:
24768901
PMCID:
PMC4104237
DOI:
10.1016/j.jhep.2014.04.009
[Indexed for MEDLINE]
Free PMC Article

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