Differential regulation of the expressions of the PGC-1α splice variants, lipins, and PPARα in heart compared to liver

Kok, Beverley; Dyck, Jason R.B.; Harris, Thurl E.; Brindley, David N.

doi:10.1194/jlr.m036624

Cited by 12 publications

(7 citation statements)

References 61 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Similarly, suppression of 50% of glycerol-3-phosphate acyltransferase activity, the fi rst step in this pathway, is also suffi cient to attenuate hepatic TG synthesis and steatosis ( 48 ). These data, taken with previous work ( 21,49 ), suggest that PAP activity is far from limiting for regulating intrahepatic TG synthesis. However, we cannot exclude that chronic defi ciency in lipin-1-mediated PAP activity leads to compensatory mechanisms for synthesizing these glycerolipids.…”

Section: Discussionsupporting

confidence: 55%

“…Our previous work demonstrated that shRNA-mediated lipin 1 knockdown in liver blunted the increased expression of genes encoding fatty acid oxidation enzymes under fasting conditions ( 14 ). This was also observed in fl d mouse liver after a shorter term fast (12 h) ( 49 ). These data, together with evidence for direct transcriptional regulation by lipin 1, suggest that lipin 1 is an inducible loss of lipin 1, rates of TG synthesis and steady-state PA, DAG, and TG levels were unchanged even under conditions of chronic lipid overload.…”

Section: Discussionmentioning

confidence: 90%

See 1 more Smart Citation

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

Schweitzer

Chen

Gan

et al. 2015

Journal of Lipid Research

View full text Add to dashboard Cite

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...

show abstract

Section: Discussionsupporting

confidence: 55%

Section: Discussionmentioning

confidence: 90%

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

Schweitzer

Chen

Gan

et al. 2015

Journal of Lipid Research

View full text Add to dashboard Cite

show abstract

“…Activation of AhR increases the expression of the transcription factor peroxisome proliferator-activated receptor-α (PPAR-α) (30), which is known to upregulate the expression of all cPT1 isoenzymes (31)(32)(33). Therefore, the expression levels of the isoenzymes cPT1A, cPT1B, and cPT1c were evaluated in the present experimental systems.…”

Section: Discussionmentioning

confidence: 99%

IDO decreases glycolysis and glutaminolysis by activating GCN2K, while it increases fatty acid oxidation by activating AhR, thus preserving CD4+ T‑cell survival and proliferation

et al. 2018

View full text Add to dashboard Cite

It is generally hypothesized in the literature that indoleamine 2,3‑dioxygenase (IDO), by degrading L‑tryptophan along the kynurenine pathway, suppresses CD4+ T‑cell function by inducing apoptosis, inhibiting proliferation and promoting differentiation towards a regulatory phenotype. These effects are either accompanied or directly lead to alterations in cell metabolism. The present study evaluated the pathways that govern the effect of IDO on the utilization of the three main energy sources in CD4+ T‑cells. Two‑way mixed lymphocyte reactions were performed with or without oleate and/or the IDO inhibitor 1‑methyl‑DL‑tryptophan. In addition, isolated CD4+ T‑cells cultured in an oleate‑containing medium were activated in the presence or not of the general control nonderepressible 2 kinase (GCN2K) activator tryptophanol. L‑tryptophan, glucose and free fatty acid consumption, cell proliferation, apoptosis and the levels of key proteins involved in IDO‑mediated signal transduction, and glucose, glutamine and free fatty acid utilization were assessed. The results indicate that IDO decreased glycolysis and glutaminolysis by activating GCN2K, resulting in activation of AMP‑activated protein kinase (AMPK). In parallel with AMPK activation, IDO‑induced activation of aryl hydrocarbon receptor increased the expression of all carnitine palmitoyltransferase I isoenzymes, leading ultimately to increased free fatty acid oxidation and preservation of CD4+ T‑cell survival and proliferation. Thus, contrary to what is generally hypothesized, in a normal environment containing fatty acids, the immunosuppressive effect of IDO may not be due to a decrease in CD4+ T‑cell survival and proliferation, since IDO supplies the required energy for cell survival and proliferation by increasing free fatty acid oxidation.

show abstract

“…Further characterisation of a Pgc-1α-b skeletal muscle-specific transgenic mouse model revealed that the improved oxidative capacity and exercise performance were directly correlated to mitochondrial volume rather than increased mitochondrial function [38]. Pgc-1α-b has also been detected in rat cardiomyocytes after fasting, an event that is dependent on cAMP signalling [39].…”

Section: Where Do We Start? Multiple Origins For Pgc-1α Transcriptsmentioning

confidence: 99%

The hitchhiker’s guide to PGC-1α isoform structure and biological functions

2015

View full text Add to dashboard Cite

Proteins of the peroxisome proliferator-activated receptor γ (PPARγ) coactivator 1 (PGC-1) family of transcriptional coactivators coordinate physiological adaptations in many tissues, usually in response to demands for higher nutrient and energy supply. Of the founding members of the family, PGC-1α (also known as PPARGC1A) is the most highly regulated gene, using multiple promoters and alternative splicing to produce a growing number of coactivator variants. PGC-1α promoters are selectively active in distinct tissues in response to specific stimuli. To date, more than ten novel PGC-1α isoforms have been reported to be expressed from a novel promoter (PGC-1α-b, PGC-1α-c), to undergo alternative splicing (NT-PGC-1α) or both (PGC-1α2, PGC-1α3, PGC-1α4). The resulting proteins display differential regulation and tissue distribution and, most importantly, exert specific biological functions. In this review we discuss the structural and functional characteristics of the novel PGC-1α isoforms, aiming to provide an integrative view of this constantly expanding system of transcriptional coactivators.

show abstract

Differential regulation of the expressions of the PGC-1α splice variants, lipins, and PPARα in heart compared to liver

Cited by 12 publications

References 61 publications

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

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

IDO decreases glycolysis and glutaminolysis by activating GCN2K, while it increases fatty acid oxidation by activating AhR, thus preserving CD4+ T‑cell survival and proliferation

The hitchhiker’s guide to PGC-1α isoform structure and biological functions

Contact Info

Product

Resources

About