Liver-specific loss of lipin-1-mediated phosphatidic acid phosphatase activity does not mitigate intrahepatic TG accumulation in mice

Abstract

This article is available online at http://www.jlr.org states and may be linked to other abnormalities in liver metabolism and function. Indeed, in a subset of individuals, hepatic steatosis can progress to liver injury, dysfunction, and failure. Intrahepatic lipid accumulation is also usually highly correlated with systemic insulin resistance, hyperglycemia, dyslipidemias, and risk of cardiovascular disease. Hepatic steatosis is extremely prevalent in obese individuals, and with the epidemic of obesity, the occurrence of nonalcoholic fatty liver disease has risen dramatically, becoming the most common cause of liver disease in the United States ( 1, 2 ).The primary storage form of lipid is TG, which, in the liver, is predominantly synthesized via the sequential acylation and dephosphorylation of glycerol-3-phosphate. In higher organisms, three genes ( Lpin1 , Lpin2 , and Lpin3 ) encode canonical enzymes that catalyze the Mg 2+ -dependent dephosphorylation of phosphatidic acid (PA) to form diacylglycerol (DAG) at the endoplasmic reticulum ( 3, 4 ). The phosphatidic acid phosphohydrolase (PAP) reaction is not only the penultimate step in TG synthesis, but also a key metabolic branch point. Alterations in PA and DAG concentrations have been linked to regulation of important intracellular signaling cascades including protein kinase C ( 5, 6 ), protein kinase A ( 7 ), ERK MAPK kinase ( 8 ), and the molecular target of rapamycin ( 9-11 ). The regulation of PA and DAG concentrations has potentially important implications for hepatic nutrient homeostasis under conditions of fasting and overnutrition. Indeed, acute RNA interference (RNAi)-mediated depletion of lipin 1 or lipin 2 in mice fed a high-fat diet attenuated hepatic steatosis and led to improvements in hepatic insulin sensitivity ( 12, 13 ).Lipins are not integral membrane proteins, and lipin 1 can translocate into the nucleus and also interact with Abstract 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 defi cient in lipin-1-encoded PAP activity in a liver-specifi c 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 signifi cantly reduced in mice with liver-specifi c lipin 1 defi ciency. 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 accum...

Lipin‐1 regulation of phospholipid synthesis maintains endoplasmic reticulum homeostasis and is critical for triple‐negative breast cancer cell survival

“…The total levels of PA, DAG, TAG, and major phospholipids, such as PC, PE, PS, and PI, remained largely unchanged, similar to a previous report that liver-specific LPIN1 knockout did not alter the global levels of PA, DAG, and phospholipids (35). The levels of PA and DAG in both HCC1806 cells expressing shLuc and shLPIN1 were very low compared with other cell types (26,35,36), implying that they are actively converted to other lipids in these cells (31,32). In contrast to unchanged total lipid levels, significant changes were observed in the compositions of most lipid classes in LPIN1knockdown cells (Fig.…”

“…4). One explanation is that these 2 lipids are actively metabolized in HCC1806 cells, which can be partially supported by our finding that both PA and DAG are in very low abundance in HCC1806 cells, as compared to those in other cells (26, 35, 36). In addition to its function as a PAP on the ER that regulates phospholipid synthesis, lipin‐1 can function as a transcriptional coactivator to regulate the expression of genes for fatty acid oxidation (20, 28).…”

Loss of lipin 1‐mediated phosphatidic acid phosphohydrolase activity in muscle leads to skeletal myopathy in mice

“…1B). That protein lacks 115 aa of the N terminus of lipin 1, and the resulting protein is deficient in PAP activity but retains transcriptional regulatory function (19,25). Accordingly, compared with WT littermate controls, PAP activity in the tissues of MCK-Lpin1 D115 mice was greatly diminished in skeletal muscle and heart (Fig.…”

How lipid droplets “TAG” along: Glycerolipid synthetic enzymes and lipid storage

“…Hepatocyte-specific lipin 1 deletion causes increased susceptibility to alcohol-induced hepatic steatosis, potentially through reduced activation of PGC-1α and fatty acid oxidation [111]. It was also shown that loss of lipin 1 PAP activity does not prevent TAG accumulation in liver in response to dietary lipid overload, possibly related to compensation by the other lipin family members expressed in liver [112]. In contrast to the results with manipulation of lipin 1 in hepatocytes, deletion of lipin 1 in myeloid cells reduces inflammation associated with alcohol-induced steatosis [113].…”