Glucocorticoids and cyclic AMP selectively increase hepatic lipin-1 expression, and insulin acts antagonistically

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 b-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

A Conserved Serine Residue Is Required for the Phosphatidate Phosphatase Activity but Not the Transcriptional Coactivator Functions of Lipin-1 and Lipin-2

“…Consistent with its tissue distribution, lipin-1 contributes the majority of PAP activity in adipose tissue and muscle (6,7). Lipin-1 is also expressed in peripheral nerve, where it is required for normal Schwann cell function (14), and in liver, where it plays a role in response to fasting and in hepatic lipoprotein secretion (5,8,15,16). Mutations in human LPIN1 have recently been detected and cause recurrent acute myoglobinuria in childhood (17), indicating a critical role for lipin-1 in human muscle function.…”

“…For example, lipin-1 and lipin-2 are both expressed in liver, although the relative levels and cell types in which they are expressed have not been definitively determined. Studies of PAP and coactivator activity in liver have thus far focused largely on lipin-1, which is required for normal induction of fasting-induced gene expression (5), and accounts for the glucocorticoid-regulated PAP activity in this tissue (8). However, recent work has also implicated lipin-2 as an important contributor to hepatic PAP activity, which is up-regulated in the liver of lipin-1-deficient mice, is induced by fasting, and is increased in obesity (9).…”

Hepatic lipid accumulation: cause and consequence of dysregulated glucoregulatory hormones

“…Glucocorticoids directly upregulate lipin-1 expression (Manmontri et al 2008), representing an intriguing mechanism driving hepatic steatosis by simultaneously decreasing lipid oxidation and increasing DNL and triglyceride esterification. By removing hairy enhancer of split 1 (Hes1), a negative regulator of PPARg expression, hepatic glucocorticoid signaling enhances PPARg expression (Revollo et al 2013, Wu et al 2015.…”

Conserved Residues in the N Terminus of Lipin-1 Are Required for Binding to Protein Phosphatase-1c, Nuclear Translocation, and Phosphatidate Phosphatase Activity

“…and Western blotting were performed as described previously using 8% gels (33), and lipin-1 was detected with a C terminus antibody (5). Alexa Fluor 680-conjugated goat anti-mouse IgG (Invitrogen) and IRDye 800-conjugated goat anti-rabbit IgG (LI-COR Biosciences) were used as the secondary antibodies.…”

“…Assays of Phosphatidate Phosphatase (PAP) Activity-PAP assays were performed essentially as described previously (33).…”