Regulation of the promoter region of the human adiponutrin/PNPLA3 gene by glucose and insulin

Rae-Whitcombe, Sharleen Margaret; Kennedy, Darnell M.; Voyles, Matt; Thompson, Matthew

doi:10.1016/j.bbrc.2010.10.106

Cited by 34 publications

(29 citation statements)

References 25 publications

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“…PNPLA3 transcription is, similarly to a number of lipogenic genes, induced by refeeding glucose and insulin (10)(11)(12), consistent with the notion that its function is not predominantly lipolytic. If PNPLA3 acts to control cycles of TAG remodeling, what would be the physiologic role of this activity?…”

Section: Pnpla3supporting

confidence: 73%

“…Moreover, the protein was shown to display a transacylase activity ( 7 ), and to prefer oleic acid (18:1n-9) as the fatty acyl moiety ( 9 ). Opposing a putative role as a lipase, PNPLA3 is induced by glucose and insulin (10)(11)(12) and is a target gene of the lipogenic transcription factors SREBP-1c and the carbohydrate responsive element binding protein, ChREBP (13)(14)(15)(16). Kumari et al ( 17 ) suggested that the protein acts as lipogenic lysophosphatidic acid (LPA) acyltransferase, converting LPA to phosphatidic acid (PA), and that the I148M substitution increases this activity.…”

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confidence: 99%

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PNPLA3 mediates hepatocyte triacylglycerol remodeling

Ruhanen

Perttilä

Hölttä‐Vuori

et al. 2014

Journal of Lipid Research

101

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a single-nucleotide polymorphism (rs738409; C>G/I148M) in the patatin-like phospholipase domain containing 3 ( PNPLA3 , adiponutrin) gene, to be strongly associated with NAFLD. A meta-analysis of 16 studies demonstrated that homozygous carriers of PNPLA3 I148M have on the average a 73% higher liver fat content than weight-matched homozygous carriers of the major allele ( 5 ). However, NAFLD associated with PNPLA3I148M is distinct from obesity-associated common NAFLD, as it is not characterized by features of the metabolic syndrome such as hyperinsulinemia or dyslipidemia ( 1, 5 ).In vitro assays using recombinant PNPLA3 have suggested that the WT PNPLA3 (PNPLA3 WT ) hydrolyzes emulsifi ed triacylglycerol (TAG) and that the I148M substitution in PNPLA3 (PNPLA3 I148M ) abolishes this activity ( 6-8 ). Moreover, the protein was shown to display a transacylase activity ( 7 ), and to prefer oleic acid (18:1n-9) as the fatty acyl moiety ( 9 ). Opposing a putative role as a lipase, PNPLA3 is induced by glucose and insulin ( 10-12 ) and is a target gene of the lipogenic transcription factors SREBP-1c and the carbohydrate responsive element binding protein, ChREBP ( 13-16 ). Kumari et al. ( 17 ) suggested that the protein acts as lipogenic lysophosphatidic acid (LPA) acyltransferase, converting LPA to phosphatidic acid (PA), and that the I148M substitution increases this activity. Because PA acts as a precursor for both phospholipids and TAGs, this provided an alternative explanation for the hepatic fat accumulation in the PNPLA3 I148M

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Section: Pnpla3supporting

confidence: 73%

mentioning

confidence: 99%

PNPLA3 mediates hepatocyte triacylglycerol remodeling

Ruhanen

Perttilä

Hölttä‐Vuori

et al. 2014

Journal of Lipid Research

101

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“…In fact, PNPLA3 is highly induced by changes in energy balance (12,15). Recently, a common nonsynonymous gene variant, the rs738409 C/G encoding an isoleucine to methionine substitution at the amino acid position 148 (I148M), has been associated with the susceptibility to nonalcoholic fatty liver disease (NAFLD) (17), a finding that was widely replicated around the world (21).…”

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confidence: 99%

Metabolic profiling reveals that PNPLA3 induces widespread effects on metabolism beyond triacylglycerol remodeling in Huh-7 hepatoma cells

Min

Sookoian

Pirola

et al. 2014

American Journal of Physiology-Gastrointestinal and Liver Physi

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Metabolic profiling reveals that PNPLA3 induces widespread effects on metabolism beyond triacylglycerol remodeling in Huh-7 hepatoma cells. Am J Physiol Gastrointest Liver Physiol 307: G66-G76, 2014. First published April 24, 2014 doi:10.1152 doi:10. /ajpgi.00335.2013 was recently associated with the susceptibility to nonalcoholic fatty liver disease, a common cause of chronic liver disease characterized by abnormal triglyceride accumulation. Although it is established that PNPLA3 has both triacylglycerol lipase and acylglycerol O-acyltransferase activities, is still unknown whether the gene has any additional role in the modulation of the human liver metabolome. To uncover the functional role of PNPLA3 on liver metabolism, we performed high-throughput metabolic profiling of PNPLA3 siRNA-silencing and overexpression of wild-type and mutant Ile148Met variants (isoleucine/methionine substitution at codon 148) in Huh-7 cells. Metabolomic analysis was performed by using GC/MS and LC/MS platforms. Silencing of PNPLA3 was associated with a global perturbation of Huh-7 hepatoma cells that resembled a catabolic response associated with protein breakdown. A significant decrease in amino-and ␥-glutamyl-amino acids and dipeptides and a significant increase in cysteine sulfinic acid, myo-inositol, lysolipids, sphingolipids, and polyunsaturated fatty acids were observed. Overexpression of the PNPLA3 Met148 variant mirrored many of the metabolic changes observed during gene silencing, but in the opposite direction. These findings were replicated by the exploration of canonical pathways associated with PNPLA3 silencing and Met148 overexpression. Overexpression of the PNPLA3 Met148 variant was associated with a 1.75-fold increase in lactic acid, suggesting a shift to anaerobic metabolism and mitochondrial dysfunction. Together, these results suggest a critical role of PNPLA3 in the modulation of liver metabolism beyond its classical participation in triacylglycerol remodeling.PNPLA3; metabolome; nonalcoholic fatty liver disease; Huh-7 cells; Ile148Met variant; systems biology THE PROTEIN ENCODED BY THE patatin-like phospholipase domain containing 3 (PNPLA3) gene, also known as adiponutrin, is a multifunctional enzyme that belongs to the IPLA2/lipase (calcium-independent phospholipase A2-epsilon) family, which has both triacylglycerol lipase and acylglycerol O-acyltransferase activities (7).

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“…Interestingly, nutritional factors, including oleic acid, C18:2 fatty acid, palmitic acid, glucose, insulin, and lactone, induce PNPLA3 [ 27 ]. In addition, the promoter activity of PNPLA3 is upregulated by glucose concentrations in a dose-dependent manner [ 28 ].…”

Section: Gene On Liver Fat Accumulationmentioning

confidence: 99%