Genetic variation in <i>PNPLA3</i> but not <i>APOC3</i> influences liver fat in non‐alcoholic fatty liver disease

Hyysalo, Jenni; Stojkovic, Ivana; Kotronen, Anna; Hakkarainen, Antti; Sevastianova, Ksenia; Makkonen, Janne; Lundbom, Nina; Rissanen, Aila; Krauss, Ronald M.; Melander, Olle; Orho‐Melander, Marju; Yki‐Järvinen, Hannele

doi:10.1111/j.1440-1746.2011.07045.x

Cited by 46 publications

(47 citation statements)

References 22 publications

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“…Later, Petersen et al [106] further demonstrated that the polymorphisms of ApoC3 (C-482T and T-455C) are associated with NAFLD and insulin resistance in Indian men. However, there is a contrary report suggested that the genetic variants in ApoC3 does not contribute to NAFLD in Finnish populations [107] . The reason regarding the divergent results remains unknown but importantly highlighted the ethnic differences in disease susceptibility.…”

Section: Genes That Affect Lipolysismentioning

confidence: 82%

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Proteomic and genomic studies of non-alcoholic fatty liver disease - clues in the pathogenesis

Lim

Dillon

Miller

2014

WJG

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Non-alcoholic fatty liver disease (NAFLD) is a widely prevalent hepatic disorder that covers wide spectrum of liver pathology. NAFLD is strongly associated with liver inflammation, metabolic hyperlipidaemia and insulin resistance. Frequently, NAFLD has been considered as the hepatic manifestation of metabolic syndrome. The pathophysiology of NAFLD has not been fully elucidated. Some patients can remain in the stage of simple steatosis, which generally is a benign condition; whereas others can develop liver inflammation and progress into non-alcoholic steatohepatitis, fibrosis, cirrhosis and hepatocellular carcinoma. The mechanism behind the progression is still not fully understood. Much ongoing proteomic researches have focused on discovering the unbiased circulating biochemical markers to allow early detection and treatment of NAFLD. Comprehensive genomic studies have also begun to provide new insights into the gene polymorphism to understand patientdisease variations. Therefore, NAFLD is considered a complex and mutifactorial disease phenotype resulting from environmental exposures acting on a susceptible polygenic background. This paper reviewed the current status of proteomic and genomic studies that have contributed to the understanding of NAFLD pathogenesis. For proteomics section, this review highlighted functional proteins that involved in: (1) transportation; (2) metabolic pathway; (3) acute phase reaction; (4) antiinflammatory; (5) extracellular matrix; and (6) immune system. In the genomic studies, this review will discuss genes which involved in: (1) lipolysis; (2) adipokines; and (3) cytokines production. Key words: Non-alcoholic fatty liver disease; Proteomics; Genomics; Metabolic syndrome; Pathophysiology Core tip: Non-alcoholic fatty liver disease (NAFLD) is a widely prevalent hepatic disorder in Western populations. NAFLD can occur as a spectrum diseases, from simple steatosis, to non-alcoholic steatohepatitis characterised by hepatocellular injury and inflammation, to cirrhosis and hepatocellular carcinoma. This paper reviewed the current status of proteomic and genomic studies that have contributed to the understanding of NAFLD pathogenesis. This review highlighted several functional proteins and genetic polymoprhisms; particular those involved in insulin resistance, triglycerides metabolism and hepatic inflammation. It is hoped that this review will offer further insights into the pathophysiology of NAFLD.

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Section: Genes That Affect Lipolysismentioning

confidence: 82%

“…Hyysalo et al [107] 2012 ApoC3 polymorphism does not associated with NAFLD in Finnish populations GCKR Santora et al [108] 2012 GCKR polymorphism is associated with NAFLD Lipogenesis pathway plays a role in NAFLD pathogenesis Tan et al [112] 2013…”

Section: Pnpla3mentioning

confidence: 99%

Proteomic and genomic studies of non-alcoholic fatty liver disease - clues in the pathogenesis

Lim

Dillon

Miller

2014

WJG

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“…Moreover, among Finnish subjects, APOC3 variants were not associated with liver fat content due to NAFLD [31]. The prevalence of variant APOC3 alleles was found to be 79.7% in Asian Indian, 66.8% in Italian, and 80% in Finnish individuals [29][30][31].…”

Section: Apolipoprotein C3 (Apoc3)mentioning

confidence: 86%

“…In contrast, in Italy and the United Kingdom, the APOC3 wild-type genotype was associated with a more favorable lipid profile but not with insulin resistance, NASH, or increased fibrosis [30]. Moreover, among Finnish subjects, APOC3 variants were not associated with liver fat content due to NAFLD [31]. The prevalence of variant APOC3 alleles was found to be 79.7% in Asian Indian, 66.8% in Italian, and 80% in Finnish individuals [29][30][31].…”

Section: Apolipoprotein C3 (Apoc3)mentioning

confidence: 87%

Significance of genetic polymorphisms in patients with nonalcoholic fatty liver disease

Miyaaki

Nakao

2017

Clin J Gastroenterol

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Because of recent advances in genetic research such as genome-wide association studies, the underlying genetic mechanisms of nonalcoholic fatty liver disease (NAFLD) pathophysiology have been elucidated. Here, we present a review of the current literature on the impact of genetic polymorphisms in patients with NAFLD. These genetic polymorphisms, which regulate lipid metabolism, glucose metabolism, and the renin-angiotensin system, are involved in NAFLD onset, steatosis, inflammation, fibrosis, and hepatocellular carcinoma (HCC). Among these genetic polymorphisms, many studies and meta-analyses have demonstrated that position 148 (rs738409 C/G) of the patatin-like phospholipase domain-containing protein (PNPLA3) is a genetic factor associated with NAFLD pathophysiological features, such as hepatic fat level, hepatic inflammation, fibrosis, and HCC. However, the impact of genetic polymorphisms on NAFLD pathophysiology appears to differ among ethnic groups. Therefore, further studies with larger sample sizes are needed for each ethnic group.

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“…In comparison, other studies included larger proportions of persons with overweight/obesity, dyslipidemia and even full blown metabolic syndrome. For instance, in the Finnish study under discussion, 10 subjects with wild-type and variant alleles of APOC3 had mean BMI of 32 and 31.5 kg/m 2 , mean waist circumferences of 106 and 103 cm, and prevalence rates of metabolic syndrome of 68% and 62%, respectively. The failure to find an association between APOC3 variants and NAFLD in one large study even when only persons with BMI < 25 kg/m 2 were analyzed militates against this explanation; 6 however, in that study, the presence of visceral obesity, which may be present despite normal BMI, was not specifically looked for.…”

mentioning

confidence: 99%

APOC3 and PNPLA3 in non‐alcoholic fatty liver disease: Need to clear the air

Duseja

Aggarwal

2012

J of Gastro and Hepatol

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function in human IBS are few, but it has been reported that the plasma concentration of kynurenic acid, which is produced through the tryptophan degradation pathway regulated by indoleamine 2,3-dioxygenase (IDO), is increased in male patients with IBS.17 Since IDO is a key enzyme regulating the metabolism of tryptophan, which plays an important role in DC function, this finding may support the hypothesis that DC function is changed in patients with IBS.The hypothesis presented in the article by Long and colleagues is attractive when we consider the mechanisms underlying PI-IBS, but several unresolved questions remain. First, were the CD86 high MHCII high LPDCs in the PI-IBS phase newly recruited from peripheral blood monocytes, or were they altered resident LPDCs? If they were a newly recruited DC subpopulation, the mechanism by which they are sustained at the mucosal site also remains unresolved. Analysis of the chemokine receptor expression patterns of both CD86 Interactions between host immune responses and intestinal bacteria are clearly important in the pathogenesis of PI-IBS. Finding the missing pieces in both mouse and human PI-IBS models should lead us to further understanding PI-IBS pathogenesis and aid the development of novel therapeutic strategies.

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Genetic variation in PNPLA3 but not APOC3 influences liver fat in non‐alcoholic fatty liver disease

Abstract: Genetic variants in PNPLA3 but not APOC3 contribute to the variance in liver fat content due to NAFLD.

Cited by 46 publications

References 22 publications

Proteomic and genomic studies of non-alcoholic fatty liver disease - clues in the pathogenesis

Proteomic and genomic studies of non-alcoholic fatty liver disease - clues in the pathogenesis

Significance of genetic polymorphisms in patients with nonalcoholic fatty liver disease

APOC3 and PNPLA3 in non‐alcoholic fatty liver disease: Need to clear the air

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