Effect of <i>PNPLA3</i> I148M polymorphism on histologically proven non‐alcoholic fatty liver disease in liver transplant recipients

Kim, Hye Young; Lee, Kwang Woong; Lee, Kyuho; Seo, Sooin; Park, Min Young; Ahn, Sung Woo; Hong, Suk Kyun; Yoon, Kyung Chul; Kim, Hyo Sin; Choi, Young Rok; Lee, Hae Won; Yi, Nam Joon; Suh, Kyung Suk

doi:10.1111/hepr.12940

Cited by 14 publications

(22 citation statements)

References 45 publications

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“…found that the G allele was a predictive factor in donors but not in recipients. These results differ from those in the previous study and those reported by Kim et al . Interestingly, however, Kim et al .…”

contrasting

confidence: 99%

“…These results differ from those in the previous study and those reported by Kim et al . Interestingly, however, Kim et al . also reported that the G allele in both the donor and recipient was the most important predictive factor; this is a very similar conclusion obtained by Dumortier et al ., who found that the development of NAFLD after LT was related to both the recipient (the “soil”) and the graft (the “seed”).…”

contrasting

confidence: 74%

“…Very recently, two similar articles in which the SNP rs738409 GG genotype in PNPLA3 was an independent and important predictor of the development of NAFLD after living‐donor LT were published in Hepatology Research . In these articles, Miyaaki et al .…”

mentioning

confidence: 99%

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Are donors or recipients a more important predictive factor for the development of non‐alcoholic fatty liver disease after liver transplantation?

Ono

2018

Hepatology Research

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contrasting

confidence: 99%

contrasting

confidence: 74%

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Are donors or recipients a more important predictive factor for the development of non‐alcoholic fatty liver disease after liver transplantation?

Ono

2018

Hepatology Research

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“…Findings yielded by a small number of studies suggest that the PNPLA3-rs738409 G allele in either the donor or the recipient could be a risk factor for NAFLD recurrence or appearance after liver transplantation. 104,105 The potential value of using genetic markers for treatment decisions pertaining to patients enrolled in NASH clinical trials remains largely unexploited. Nonetheless, it is expected that this specific clinical application will be explored in the near future as the use of novel drugs for the treatment of NASH becomes available in the market.…”

Section: Genetics Of Nafld and Precision Medicinementioning

confidence: 99%

Genetics of Nonalcoholic Fatty Liver Disease: From Pathogenesis to Therapeutics

Sookoian

Pirola

2019

Semin Liver Dis

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Here, the authors review the remarkable genetic discoveries that have illuminated the biology of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). The authors integrate genes associated with NAFLD and NASH into regulatory pathways to elucidate the disease pathogenesis. They review the evidence for molecular mediators of chronic liver damage, which suggests that convergent pathophenotypes, including inflammation and fibrosis, share common genetic modifiers. They further demonstrate that genes involved in the genetic susceptibility of NAFLD and NASH participate in cross-phenotype associations with diseases of the metabolic syndrome, including type 2 diabetes, obesity, and cardiovascular disease. However, immune-related loci associated with NAFLD and NASH exhibit some level of pleiotropy influencing disparate phenotypes, such as premature birth or sepsis. They finally focus on the translation of current genetic knowledge of NAFLD and NASH toward precision medicine. They provide evidence of genetic findings that can be leveraged to identify therapeutic targets.

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“…Mobilization of retinol from lipid droplets in HSC is catalyzed by REHs, and several enzymes are implicated in this process, including adipose triglyceride lipase (ATGL/PNPLA2) [ 44 ], patatin-like phospholipase domain-containing 3 (PNPLA3) [ 44 , 45 , 46 ], and hormone-sensitive lipase (HSL) [ 47 , 48 ]. Interestingly, genetic studies have identified the PNPLA3-I148M variant as a prominent genetic factor associated with NAFLD, and even more prominently with disease progression within NAFLD to NASH and NASH-associated cirrhosis [ 49 , 50 , 51 ]. PNPLA3 affects vitamin A homeostasis, as will be discussed in more detail in the following sections.…”

Section: Vitamin a Uptake Storage And Metabolismmentioning

confidence: 99%

Disturbed Vitamin A Metabolism in Non-Alcoholic Fatty Liver Disease (NAFLD)

et al. 2017

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Vitamin A is required for important physiological processes, including embryogenesis, vision, cell proliferation and differentiation, immune regulation, and glucose and lipid metabolism. Many of vitamin A’s functions are executed through retinoic acids that activate transcriptional networks controlled by retinoic acid receptors (RARs) and retinoid X receptors (RXRs).The liver plays a central role in vitamin A metabolism: (1) it produces bile supporting efficient intestinal absorption of fat-soluble nutrients like vitamin A; (2) it produces retinol binding protein 4 (RBP4) that distributes vitamin A, as retinol, to peripheral tissues; and (3) it harbors the largest body supply of vitamin A, mostly as retinyl esters, in hepatic stellate cells (HSCs). In times of inadequate dietary intake, the liver maintains stable circulating retinol levels of approximately 2 μmol/L, sufficient to provide the body with this vitamin for months. Liver diseases, in particular those leading to fibrosis and cirrhosis, are associated with impaired vitamin A homeostasis and may lead to vitamin A deficiency. Liver injury triggers HSCs to transdifferentiate to myofibroblasts that produce excessive amounts of extracellular matrix, leading to fibrosis. HSCs lose the retinyl ester stores in this process, ultimately leading to vitamin A deficiency. Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome and is a spectrum of conditions ranging from benign hepatic steatosis to non-alcoholic steatohepatitis (NASH); it may progress to cirrhosis and liver cancer. NASH is projected to be the main cause of liver failure in the near future. Retinoic acids are key regulators of glucose and lipid metabolism in the liver and adipose tissue, but it is unknown whether impaired vitamin A homeostasis contributes to or suppresses the development of NAFLD. A genetic variant of patatin-like phospholipase domain-containing 3 (PNPLA3-I148M) is the most prominent heritable factor associated with NAFLD. Interestingly, PNPLA3 harbors retinyl ester hydrolase activity and PNPLA3-I148M is associated with low serum retinol level, but enhanced retinyl esters in the liver of NAFLD patients. Low circulating retinol in NAFLD may therefore not reflect true “vitamin A deficiency”, but rather disturbed vitamin A metabolism. Here, we summarize current knowledge about vitamin A metabolism in NAFLD and its putative role in the progression of liver disease, as well as the therapeutic potential of vitamin A metabolites.

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Effect of PNPLA3 I148M polymorphism on histologically proven non‐alcoholic fatty liver disease in liver transplant recipients

Abstract: PNPLA3 I148M polymorphism can significantly affect histologically proven NAFLD at 1 year post-LT.

Cited by 14 publications

References 45 publications

Are donors or recipients a more important predictive factor for the development of non‐alcoholic fatty liver disease after liver transplantation?

Are donors or recipients a more important predictive factor for the development of non‐alcoholic fatty liver disease after liver transplantation?

Genetics of Nonalcoholic Fatty Liver Disease: From Pathogenesis to Therapeutics

Disturbed Vitamin A Metabolism in Non-Alcoholic Fatty Liver Disease (NAFLD)

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