The APOC3 T-455C and C-482T promoter region polymorphisms are not associated with the severity of liver damage independently of PNPLA3 I148M genotype in patients with nonalcoholic fatty liver

Valenti, Luca; Nobili, Valério; Al-Serri, Ahmad; Rametta, Raffaela; Leathart, Julian; Zappa, Marco Antonio; Dongiovanni, Paola; Fracanzani, Anna Ludovica; Alterio, Arianna; Roviaro, Giancarlo; Daly, Ann K.; Fargion, Silvia; Day, Christopher P.

doi:10.1016/j.jhep.2011.03.035

Cited by 76 publications

(67 citation statements)

References 35 publications

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“…This finding was reproducible in humans harboring either or both of the C-482T and T-455C alleles in different ethnic groups, including African Americans, European Americans, Hispanics, Southern Europeans, Italians, and Chinese (35,36,38,57,58). Further physiological underpinning of the dissociation between APOC3 and NAFLD is derived from the clinical study by Zampino et al (59), who evaluated the genetic influence of APOC3 polymorphism on steatosis in an Italian patient population with chronic hepatitis C infection.…”

Section: Discussionsupporting

confidence: 57%

APOC3 Protein Is Not a Predisposing Factor for Fat-induced Nonalcoholic Fatty Liver Disease in Mice

Cheng

Yamauchi

Lee

et al. 2017

Journal of Biological Chemistry

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Edited by Jeffrey E. PessinNonalcoholic fatty liver disease (NAFLD), characterized by excessive fat accumulation in liver, is prevalent in obesity. Genetic factors that link obesity to NAFLD remain obscure. Apolipoprotein C3 (APOC3) is a lipid-binding protein with a pivotal role in triglyceride metabolism. Humans with APOC3 gain-of-function mutations and mice with APOC3 overproduction are associated with hypertriglyceridemia. Nonetheless, it remains controversial whether APOC3 is culpable for diet-induced NAFLD. To address this fundamental issue, we fed APOC3-transgenic and wild-type littermates a high fructose diet or high fat diet, followed by determination of the effect of APOC3 on hepatic lipid metabolism and inflammation and the progression of NAFLD. To gain mechanistic insight into NAFLD, we determined the impact of APOC3 on hepatic triglyceride synthesis and secretion versus fatty acid oxidation. APOC3-transgenic mice were hypertriglyceridemic, culminating in marked elevation of triglycerides, cholesterols, and nonesterified fatty acids in plasma. Despite the prevailing hypertriglyceridemia, APOC3-transgenic mice, relative to wild-type littermates, had similar weight gain and hepatic lipid content without alterations in hepatic expression of key genes involved in triglyceride synthesis and secretion and fatty acid oxidation. APOC3-transgenic and wild-type mice had similar Kupffer cell content without alterations in hepatic expression of pro-and anti-inflammatory cytokines. APOC3 neither exacerbated dietinduced adiposity nor aggravated the degree of steatosis in high fructose or high fat-fed APOC3-transgenic mice. These effects ensued independently of weight gain even after 10-month high fat feeding. We concluded that APOC3, whose dysregulation is liable for hypertriglyceridemia, is not a predisposing factor for linking overnutrition to NAFLD in obesity. Nonalcoholic fatty liver disease (NAFLD)4 is characterized by excessive lipid deposition in the liver of subjects with little alcohol consumption. Patients with NAFLD are at heightened risk of developing steatohepatitis with potential complications of fibrosis and cirrhosis (1-4). Currently, NAFLD affects about 30% of the general population, and its prevalence is increasing along with the rising epidemic of obesity in both adults and children (1, 5-10). Although it is known that NAFLD results from increased lipogenesis and decreased fatty acid oxidation in the liver, accompanied often by hepatic overproduction of TG-rich very low density lipoprotein (VLDL-TG), genetic factors that tip the balance of these three intertwining pathways in hepatic lipid metabolism at the expense of NAFLD are incompletely characterized.Apolipoprotein C3 (APOC3) (79 amino acids in length) is one of the most abundant apolipoproteins in the blood, where it is present as an exchangeable moiety between high density lipoproteins (HDLs) and triglyceride (TG)-rich particles, such as VLDL and chylomicrons (11). Secreted mainly from the liver and to a lesser extent from the intestine, AP...

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Section: Discussionsupporting

confidence: 57%

APOC3 Protein Is Not a Predisposing Factor for Fat-induced Nonalcoholic Fatty Liver Disease in Mice

Cheng

Yamauchi

Lee

et al. 2017

Journal of Biological Chemistry

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“…Subjects with NAFLD also exhibited marked insulin resistance [29]. 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].…”

Section: Apolipoprotein C3 (Apoc3)mentioning

confidence: 95%

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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“…The results differed depending on individual foods or bacteria. For example, Wasabia japonica leaf, 7 rice extract, 8 a strain of Bifidobacterium bifidum, 9 and garlic 10 suppressed mucosal inflammation in the Accepted for publication 9 February 2012.…”

Section: Masashi Matsushima and Atsushi Takagimentioning

confidence: 99%

“…[6][7][8][9] In one of these studies that included 1228 African American, 843 European American and 426 Hispanic subjects who had participated in the Dallas Heart Study, neither of the two APOC3 mutant alleles was associated with homeostatic model of insulin resistance (HOMA-IR), or hepatic fat content. 6 The variants were also not associated with HOMA-IR in another additional large cohort, namely participants in the Atherosclerosis Risk in Communities Study; liver fat was not determined in this group.…”

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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The APOC3 T-455C and C-482T promoter region polymorphisms are not associated with the severity of liver damage independently of PNPLA3 I148M genotype in patients with nonalcoholic fatty liver

Cited by 76 publications

References 35 publications

APOC3 Protein Is Not a Predisposing Factor for Fat-induced Nonalcoholic Fatty Liver Disease in Mice

APOC3 Protein Is Not a Predisposing Factor for Fat-induced Nonalcoholic Fatty Liver Disease in Mice

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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