TORC2 Regulates Hepatic Insulin Signaling via a Mammalian Phosphatidic Acid Phosphatase, LIPIN1

Abstract

TORC2 is a major transcriptional coactivator for hepatic glucose production. Insulin impedes gluconeogenesis by inhibiting TORC2 via SIK2-dependent phosphorylation at Ser171. Interruption of this process greatly perturbs hepatic glucose metabolism, thus promoting hyperglycemia in rodents. Here, we show that hyperactivation of TORC2 would exacerbate insulin resistance by enhancing expression of LIPIN1, a mammalian phosphatidic acid phosphatase for diacylglycerol (DAG) synthesis. Diet-induced or genetic obesity increases LIPIN1 expression in mouse liver, and TORC2 is responsible for its transcriptional activation. While overexpression of LIPIN1 disturbs hepatic insulin signaling, knockdown of LIPIN1 ameliorates hyperglycemia and insulin resistance by reducing DAG and PKCvarepsilon activity in db/db mice. Finally, TORC2-mediated insulin resistance is partially rescued by concomitant knockdown of LIPIN1, confirming the critical role of LIPIN1 in the perturbation of hepatic insulin signaling. These data propose that dysregulation of TORC2 would further exaggerate insulin resistance and promote type 2 diabetes in a LIPIN1-dependent manner.

Isolation of Novel Animal Cell Lines Defective in Glycerolipid Biosynthesis Reveals Mutations in Glucose-6-phosphate Isomerase

“…The PAP1 protein can be modified by phosphorylation in a mammalian target of rapamycin-dependent manner (45), although it is unclear what effect this has on its activity. On the other hand, it has recently been shown that the LPIN1 gene is regulated by TORC2 (46). TORC2 is a target of phosphorylation by AMP kinase, controlling TORC2 gene regulator activity (47,48).…”

Hepatic Gluconeogenesis Is Enhanced by Phosphatidic Acid Which Remains Uninhibited by Insulin in Lipodystrophic Agpat2−/− Mice

“…Two previous reports have attempted to demonstrate a role of PA in insulin signaling (34,35). Zhang et al (35) observed an increase in total LPA, PA, and DAG levels and also a modest increase in glucose output in primary mouse hepatocytes from WT mice overexpressing GPAT1.…”

“…All three lipin isoforms, lipin 1, lipin 2, and lipin 3, are known to be expressed in the liver (36). Ryu et al (34) showed that overexpression of lipin 1 in WT hepatocytes leads to an increase in DAG levels (34). This did not regulate the phosphorylation of Akt, a key molecule for insulin signaling.…”

Identification of the transcript isoforms and expression characteristics for chicken Lpin1

“…Lpin1 RNAi in db/db mice had not showed significant effect on plasma TG and INS level (Ryu et al, 2009). Our study showed that chicken Lpin1 gene mRNA expression level was significantly negatively correlated with serum HDL and total CHO level (P , 0.05), whereas had no significant correlation with serum INS, TG and GLU level.…”

“…Ryu et al (2009) found that fasting, high-fat diet and db/db mouse enhanced the expression of hepatic Lpin1 transcript and protein. Similar to the fasting effect in mice, our study showed that 30% energy restriction increased the relative expression of chicken total Lpin1 in both adipose tissue and hepatic tissues.…”