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

Garg, Abhimanyu; Horton, Jay D.; Agarwal, Anil K.

doi:10.1074/jbc.m113.530998

Cited by 17 publications

(33 citation statements)

References 45 publications

(37 reference statements)

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“…This gene encodes the lysophosphatidic acid (LPA) receptor 2, which belongs to family I of the G-protein receptors and functions to mobilize calcium in response to LPA. Recently, LPA signaling was shown to impair glucose homeostasis and inhibit insulin secretion in obese mice fed a high-fat diet [39], and is involved with hepatic gluconeogenesis and insulin resistance [40]. Interestingly, the rs10401969 risk allele was associated with significantly higher glucose levels with a trend for higher insulin in the minor allele homozygotes (Supplemental Table 3).…”

Section: Discussionmentioning

confidence: 99%

Genome-wide analysis of hepatic lipid content in extreme obesity

DiStefano

Kingsley

Wood³

et al. 2014

Acta Diabetol

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Individuals with type 2 diabetes have an increased risk of developing nonalcoholic fatty liver disease (NAFLD), and NAFLD patients are also at greater risk for developing type 2 diabetes. Although the relationship between type 2 diabetes and NAFLD is highly interconnected, the pathogenic mechanisms linking the two diseases are poorly understood. The goal of this study was to identify genetic determinants of hepatic lipid accumulation through association analysis using histological phenotypes in obese individuals. Using the Illumina HumanOmniExpress BeadChip assay, we genotyped 2300 individuals on whom liver biopsy data were available. We analyzed total bilirubin levels, which are linked to fatty liver in severe obesity, and observed the strongest evidence for association with rs4148325 in UGT1A (P<5.0 × 10−93), replicating previous findings. We assessed hepatic fat level and found strong evidence for association with rs4823173, rs2896019, and rs2281135, all located in PNPLA3 and rs10401969 in SUGP1. Analysis of liver transcript levels of 20 genes residing at the SUGP1/NCAN locus identified a 1.6-fold change in expression of the LPAR2 gene in fatty liver. We also observed suggestive evidence for association between low-grade fat accumulation and rs10859525 and rs1294908, located upstream from SOCS2 and RAMP3, respectively. SOCS2 was differentially expressed between fatty and normal liver. These results replicate findings for several hepatic phenotypes in the setting of extreme obesity and implicate new loci that may play a role in the pathophysiology of hepatic lipid accumulation.

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Section: Discussionmentioning

confidence: 99%

Genome-wide analysis of hepatic lipid content in extreme obesity

DiStefano

Kingsley

Wood³

et al. 2014

Acta Diabetol

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“…In our own observations in Agpat2 -/-mice, elevated levels of some types of phosphatidic acid (such as, C16:0/18:1 and C18:1/20:4) can increase hepatic glucose production. 138 Similar mechanisms might be involved in patients with generalized or regional (for example, truncal) obesity, in whom circulating triglycerides are diverted to ectopic sites, owing to adipocytes already being overfilled with triglycerides. However, some unique metabolic derange ments are observed in patients with CGL.…”

Section: Metabolic Complications In Cglmentioning

confidence: 97%

Congenital generalized lipodystrophies—new insights into metabolic dysfunction

2015

Self Cite

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Congenital generalized lipodystrophy (CGL) is a heterogeneous autosomal recessive disorder characterized by a near complete lack of adipose tissue from birth and, later in life, the development of metabolic complications, such as diabetes mellitus, hypertriglyceridaemia and hepatic steatosis. Four distinct subtypes of CGL exist: type 1 is associated with AGPAT2 mutations; type 2 is associated with BSCL2 mutations; type 3 is associated with CAV1 mutations; and type 4 is associated with PTRF mutations. The products of these genes have crucial roles in phospholipid and triglyceride synthesis, as well as in the formation of lipid droplets and caveolae within adipocytes. The predominant cause of metabolic complications in CGL is excess triglyceride accumulation in the liver and skeletal muscle owing to the inability to store triglycerides in adipose tissue. Profound hypoleptinaemia further exacerbates metabolic derangements by inducing a voracious appetite. Patients require psychological support, a low-fat diet, increased physical activity and cosmetic surgery. Aside from conventional therapy for hyperlipidaemia and diabetes mellitus, metreleptin replacement therapy can dramatically improve metabolic complications in patients with CGL. In this Review, we discuss the molecular genetic basis of CGL, the pathogenesis of the disease's metabolic complications and therapeutic options for patients with CGL.

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“…PA is a lipid second messenger involved in membrane transport and several important signaling cascades including mammalian target of rapamycin (mTOR). In addition, several PA species may be involved in insulin signaling1011. Di-16:0 PA dampens protein kinase B (Akt) phosphorylation in insulin-stimulated hepatocytes by disrupting the interaction between mTOR and rapamycin-insensitive companion of mTOR (rictor)10.…”

mentioning

confidence: 99%

“…Di-16:0 PA dampens protein kinase B (Akt) phosphorylation in insulin-stimulated hepatocytes by disrupting the interaction between mTOR and rapamycin-insensitive companion of mTOR (rictor)10. Additionally, 16:0/18:1 PA and 18:1/20:4 PA enhance hepatic glucose production in AGPAT2 −/− mice by elevating the expression of glucose-6-phosphatase and phosphoenolpyruvate carboxykinase, resulting in hyperglycemia11. However, the functions of PA species from different enzymatic reactions in hepatic steatosis have not been demonstrated.…”

mentioning

confidence: 99%

Phospholipase D1 deficiency in mice causes nonalcoholic fatty liver disease via an autophagy defect

Hur

Park

Dall’Armi

et al. 2016

Sci Rep

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Nonalcoholic fatty liver disease (NAFLD) is characterized by the accumulation of triglycerides (TG) as lipid droplets in the liver. Although lipid-metabolizing enzymes are considered important in NAFLD, the involvement of phospholipase D1 (PLD1) has not yet been studied. Here, we show that the genetic ablation of PLD1 in mice induces NAFLD due to an autophagy defect. PLD1 expression was decreased in high-fat diet-induced NAFLD. Subsequently, PLD1 deficiency led to an increase in hepatic TGs and liver weight. Autophagic flux was blocked in Pld1−/− hepatocytes, with decreased β-oxidation rate, reduced oxidation-related gene expression, and swollen mitochondria. The dynamics of autophagy was restored by treatment with the PLD product, phosphatidic acid (PA) or adenoviral PLD1 expression in Pld1−/− hepatocytes, confirming that lysosomal PA produced by PLD1 regulates autophagy. Notably, PLD1 expression in Pld1−/− liver significantly reduced hepatic lipid accumulation, compared with Pld1−/− liver. Thus, PLD1 plays an important role in hepatic steatosis via the regulation of autophagy.

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

Abstract: Background: Lipodystrophic Agpat2Ϫ/Ϫ mice are severely diabetic and insulin resistant.

Cited by 17 publications

References 45 publications

Genome-wide analysis of hepatic lipid content in extreme obesity

Genome-wide analysis of hepatic lipid content in extreme obesity

Congenital generalized lipodystrophies—new insights into metabolic dysfunction

Phospholipase D1 deficiency in mice causes nonalcoholic fatty liver disease via an autophagy defect

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