Genetic Polymorphisms of the Human PNPLA3 Gene Are Strongly Associated with Severity of Non-Alcoholic Fatty Liver Disease in Japanese

Kawaguchi, Takahisa; Sumida, Yoshio; Umemura, Atsushi; Matsuo, Keitaro; Takahashi, Meiko; Takamura, Toshinari; Yasui, Kohichiroh; Saibara, Toshiji; Hashimoto, Etsuko; Kawanaka, Miwa; Watanabe, Sumio; Kawata, Satoshi; Imai, Yumiko; Kokubo, Mitsunori; Shima, Toshihide; Park, Hyohun; Tanaka, Hideo; Tajima, Kazuo; Yamada, Ryo; Matsuda, Fumihiko

doi:10.1371/journal.pone.0038322

Cited by 236 publications

(227 citation statements)

References 24 publications

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“…Relatively lower levels of TRIB1 expression due to the minor allele of rs6982502 might have resulted in increased levels of plasma lipid and progression to hepatic steatosis. While TRIB1 has not been significantly associated with NAFLD diagnosed by computed tomography (CT) (Romeo et al 2008, Kawaguchi et al 2012, the GWAS of plasma AST levels in Europe found a significant association with the SNP, rs2954021, which localized in the same LD block as rs17321515 (Chambers et al 2011). A weak association between rs2954021 and hepatic steatosis was also identified (Chambers et al 2011).…”

Section: Discussionmentioning

confidence: 99%

TRIB1 downregulates hepatic lipogenesis and glycogenesis via multiple molecular interactions

Ishizuka¹,

Nakayama²,

Ogawa³

et al. 2014

Journal of Molecular Endocrinology

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Mammalian tribbles homolog 1 (TRIB1) regulates hepatic lipogenesis and is genetically associated with plasma triglyceride (TG) levels and cholesterol, but the molecular mechanisms remain obscure. We explored these mechanisms in mouse livers transfected with a TRIB1 overexpression, a shRNA template or a control (LacZ) adenovirus vector. The overexpression of TRIB1 reduced, whereas induction of the shRNA template increased, plasma glucose, TG, and cholesterol and simultaneously hepatic TG and glycogen levels. The involvement of TRIB1 in hepatic lipid accumulation was supported by the findings of a human SNP association study. A TRIB1 SNP, rs6982502, was identified in an enhancer sequence, modulated enhancer activity in reporter gene assays, and was significantly (PZ9.39!10 K7 ) associated with ultrasonographically diagnosed nonalcoholic fatty liver disease in a population of 5570 individuals. Transcriptome analyses of mouse livers revealed significant modulation of the gene sets involved in glycogenolysis and lipogenesis. Enforced TRIB1 expression abolished CCAAT/enhancer binding protein A (CEBPA), CEBPB, and MLXIPL proteins, whereas knockdown increased the protein level. Levels of TRIB1 expression simultaneously affected MKK4 (MAP2K4), MEK1 (MAP2K1), and ERK1/2 (MAPK1/3) protein levels and the phosphorylation of JNK, but not of ERK1/2. Pull-down and mammalian two-hybrid analyses revealed novel molecular interaction between TRIB1 and a hepatic lipogenic master regulator, MLXIPL. Co-expression of TRIB1 and CEBPA or MLXIPL reduced their protein levels and proteasome inhibitors attenuated the reduction. These data suggested that the modulation of TRIB1 expression affects hepatic lipogenesis and glycogenesis through multiple molecular interactions.

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Section: Discussionmentioning

confidence: 99%

TRIB1 downregulates hepatic lipogenesis and glycogenesis via multiple molecular interactions

Ishizuka¹,

Nakayama²,

Ogawa³

et al. 2014

Journal of Molecular Endocrinology

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“…Familial clustering and ethnic differences in susceptibility indicate that genetic factors may be important risk determinants for development and progression of NAFLD/ NASH [32][33][34][35][36]. Variation in the enzyme adiponutrin (patatin-like phospholipase domain-containing protein 3; PNPLA3) is a major genetic determinant of hepatic steatosis and fibrosis [33][34][35].…”

Section: Clinical Featuresmentioning

confidence: 99%

“…Variation in the enzyme adiponutrin (patatin-like phospholipase domain-containing protein 3; PNPLA3) is a major genetic determinant of hepatic steatosis and fibrosis [33][34][35].…”

Section: Clinical Featuresmentioning

confidence: 99%

Evidence-based clinical practice guidelines for nonalcoholic fatty liver disease/nonalcoholic steatohepatitis

et al. 2015

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Nonalcoholic fatty liver disease (NAFLD) is currently the most common cause of chronic liver disease in industrialized countries worldwide, and has become a serious public health issue not only in Western countries but also in many Asian countries including Japan. Within the wide spectrum of NAFLD, nonalcoholic steatohepatitis (NASH) is a progressive form of disease, which often develops into liver cirrhosis and increases the risk of hepatocellular carcinoma. In turn, a large proportion of NAFLD/NASH is the liver manifestation of metabolic syndrome, suggesting that NAFLD/NASH plays a key role in the pathogenesis of systemic atherosclerotic diseases. Currently, a definite diagnosis of NASH requires liver biopsy, though various noninvasive measures are under development. The mainstays of prevention and treatment of NAFLD/NASH include dietary restriction and exercise; however, pharmacological approaches are often necessary.Currently, vitamin E and thiazolidinedione derivatives are the most evidence-based therapeutic options, although the clinical evidence for long-term efficacy and safety is limited. This practice guideline for NAFLD/NASH, established by the Japanese Society of Gastroenterology in cooperation with The Japan Society of Hepatology, covers lines of clinical evidence reported internationally in the period starting from 1983 to January 2012, and each clinical question was evaluated using the GRADE system. Based on the primary release of the full version in Japanese, this English summary provides the core essentials of this clinical practice guideline comprising the definition, diagnosis, and current therapeutic recommendations for NAFLD/NASH in Japan.

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“…Polymorphisms of PNPLA3 gene have been found to be strongly associated with the pathogenic status of NAFLD in different populations [91][92][93] . PNPLA3 gene, encoding adiponutrin is known to have lipase activity in vitro and has been found to be involved in glucose and lipid metabolism [91] .…”

Section: Genes That Affect Lipolysismentioning

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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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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Genetic Polymorphisms of the Human PNPLA3 Gene Are Strongly Associated with Severity of Non-Alcoholic Fatty Liver Disease in Japanese

Cited by 236 publications

References 24 publications

TRIB1 downregulates hepatic lipogenesis and glycogenesis via multiple molecular interactions

TRIB1 downregulates hepatic lipogenesis and glycogenesis via multiple molecular interactions

Evidence-based clinical practice guidelines for nonalcoholic fatty liver disease/nonalcoholic steatohepatitis

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

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