Abstract
Glucocorticoids (GCs) increase hepatic phosphatidate phosphatase (PAP1) activity. This is important in enhancing the liver's capacity for storing fatty acids as triacylglycerols (TAGs) that can be used subsequently for beta-oxidation or VLDL secretion. PAP1 catalyzes the conversion of phosphatidate to diacylglycerol, a key substrate for TAG and phospholipid biosynthesis. PAP1 enzymes in liver include lipin-1A and -1B (alternatively spliced isoforms) and two distinct gene products, lipin-2 and lipin-3. We determined the mechanisms by which the composite PAP1 activity is regulated using rat and mouse hepatocytes. Levels of lipin-1A and -1B mRNA were increased by dexamethasone (dex; a synthetic GC), and this resulted in increased lipin-1 synthesis, protein levels, and PAP1 activity. The stimulatory effect of dex on lipin-1 expression was enhanced by glucagon or cAMP and antagonized by insulin. Lipin-2 and lipin-3 mRNA were not increased by dex/cAMP, indicating that increased PAP1 activity is attributable specifically to enhanced lipin-1 expression. This work provides the first evidence for the differential regulation of lipin activities. Selective lipin-1 expression explains the GC and cAMP effects on increased hepatic PAP1 activity, which occurs in hepatic steatosis during starvation, diabetes, stress, and ethanol consumption.
Highlights
Glucocorticoids (GCs) increase hepatic phosphatidate phosphatase (PAP1) activity
PAP2 is commonly known as a family of lipid phosphate phosphatases (LPPs) that dephosphorylate a variety of lipid phosphate esters
Increases in hepatic PAP1 occur in response to dietary modification in rodents, for instance, when glucose or starch is replaced by fructose, sorbitol, glycerol, or ethanol [15], and these effects are exaggerated by high-fat feeding [16]
Summary
Glucocorticoids (GCs) increase hepatic phosphatidate phosphatase (PAP1) activity. This is important in enhancing the liver’s capacity for storing fatty acids as triacylglycerols (TAGs) that can be used subsequently for b-oxidation or VLDL secretion. Subsequent work with rat hepatocytes demonstrated that the glucocorticoid (GC) effect in increasing PAP1 activity was synergized by glucagon and inhibited by insulin [8, 9]. We showed that these GCinduced increases in PAP1 activity provide the extra capacity for the liver to sequester excess FAs as TAG when these FAs are not immediately required for b-oxidation [5]. Increases in hepatic PAP1 occur in response to dietary modification in rodents, for instance, when glucose or starch is replaced by fructose, sorbitol, glycerol, or ethanol [15], and these effects are exaggerated by high-fat feeding [16] These changes in PAP1 are Mammalian phosphatidate phosphatase (PAP1) activity is Mg21-dependent and is inhibited by N-ethylmaleimide. Sariahmetoglu contributed to this work. 2 To whom correspondence should be addressed
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