Genetics of Non-Alcoholic Fatty Liver and Cardiovascular Disease: Implications for Therapy?

Chandrasekharan, K.; Alazawi, William

doi:10.3389/fphar.2019.01413

Cited by 21 publications

(20 citation statements)

References 85 publications

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“…52,53 Polygenic risk scores may predict the risk of NAFLD development and progression as well as cardiovascular disease. 52,[54][55][56][57] The Link between NAFLD and Risk of Cardiovascular Complications…”

Section: Pathophysiology Of Steatosismentioning

confidence: 99%

Nonalcoholic Fatty Liver Disease and Cardiovascular Disease: Overlapping Mechanisms

et al. 2021

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Nonalcoholic fatty liver disease (NAFLD) denotes a condition with excess fat in the liver. The prevalence of NAFLD is increasing, averaging > 25% of the Western population. In 25% of the patients, NAFLD progresses to its more severe form: nonalcoholic steatohepatitis and >25% of these progress to cirrhosis following activation of inflammatory and fibrotic processes. NAFLD is associated with obesity, type 2 diabetes, and the metabolic syndrome and represents a considerable and increasing health burden. In the near future, NAFLD cirrhosis is expected to be the most common cause for liver transplantation. NAFLD patients have an increased risk of developing cardiovascular disease as well as liver-related morbidity. In addition, hepatic steatosis itself appears to represent an independent cardiovascular risk factor. In the present review, we provide an overview of the overlapping mechanisms and prevalence of NAFLD and cardiovascular disease.

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Section: Pathophysiology Of Steatosismentioning

confidence: 99%

Nonalcoholic Fatty Liver Disease and Cardiovascular Disease: Overlapping Mechanisms

et al. 2021

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“…The common rs641738C > T variant linked to the 3’ untranslated region of the MBOAT7 has been associated with a reduction in MBOAT7 intracellular hepatic expression at the mRNA and protein level. Moreover, down‐regulation of MBOAT7 regardless of genetic background is a maladaptive response to hyper‐insulinaemia promoting intracellular hepatic fat deposition as a result of impaired arachidonoyl‐phosphatidylinositol which leads to the conversion of saturated lysophosphatidylinositol to triglycerides, enhancing lipogenesis, 37,38 therefore, possibly increasing the risk of hepatic steatosis, NASH, hepatic fibrosis stage F2‐F4 and HCC without advanced fibrosis 39 . Figure 2 outlines a proposed model demonstrating potential effects of rs641738C > T near MBOAT7 on the liver in MAFLD.…”

Section: Effects Of Rs641738c > T Variant Near Membrane‐bound O‐acyltmentioning

confidence: 99%

Genetic predisposition in metabolic‐dysfunction‐associated fatty liver disease and cardiovascular outcomes—Systematic review

Ismaiel

Dumitraşcu

2020

Eur J Clin Investigation

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Background: Despite the demonstrated increased cardiovascular (CV) risk associated with metabolic-dysfunction-associated fatty liver disease (MAFLD), genetic variants predisposing to MAFLD were not constantly associated with CV events. Recently, rs641738C > T near membrane-bound O-acyltransferase domain-containing 7 (MBOAT7) has been studied in MAFLD and CV outcomes. Therefore, we aimed to evaluate the association between rs641738C > T in the presence and severity of hepatic steatosis, fibrosis, biochemical markers and progression to hepatocellular carcinoma (HCC), in addition to CV outcomes in MAFLD. Materials and Methods: An electronic search on PubMed, Embase and Cochrane Library for articles published till 23 March 2020 was systematically performed. Articles were screened, and data extracted from eligible studies by two reviewers independently. Results: Studies conducted on adults with MAFLD involving European, Hispanic and African American populations evaluating rs641738 reported reduced hepatic expression of MBOAT7, increased hepatic fat content, severity of MAFLD, susceptibility to develop NASH, advanced fibrosis and HCC in adults. However, most articles involving Asian individuals contradicted these findings. Studies involving obese children associated rs641738 with increased plasma alanine aminotransferase (ALT) levels, while its association with MAFLD remains inconsistent. The rs641738 variant was assessed as a MAFLD susceptibility gene in coronary artery disease (CAD) reporting neutral effects. Conclusions: Despite inconclusive results in Asian populations, rs641738C > T near MBOAT7 is associated with increased hepatic fat, MAFLD severity, susceptibility to develop NASH, advanced fibrosis and HCC in adults from Caucasian, Hispanic and African American ethnicities with MAFLD, as well as elevated ALT levels in children, while exerting neutral effects in CAD.

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“…NAFLD is a complex disease that is an intricate interplay of intertwined genetic and environmental factors [3][4][5]. On one hand, the Genome Wide Association Studies (GWAS) have identified variants in the genes PNPLA3, TM6SF2, GCKR, MBOAT7 and HSD17B13 that seem to be associated with susceptibility to and/or progression of NAFLD [6].…”

Section: Introductionmentioning

confidence: 99%

Emergent properties of HNF4α-PPARγ network may drive consequent phenotypic plasticity in NAFLD

Sahoo

Singh

Chakraborty

et al. 2020

Preprint

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Non-Alcoholic Fatty Liver Disease (NAFLD) is the most common form of chronic liver disease in adults and children. It is characterized by excessive accumulation of lipids in the hepatocytes of patients without any excess alcohol intake. With a global presence of 24% and limited therapeutic options, the disease burden of NAFLD is increasing. Thus, it becomes imperative to attempt to understand the dynamics of disease progression at a systems-level. Here, we decode the emergent dynamics of underlying gene regulatory networks that have been identified to drive the initiation and progression of NAFLD. We have developed a mathematical model to elucidate the dynamics of the HNF4α-PPARγ gene regulatory network. Our simulations reveal that this network can enable multiple co-existing phenotypes under certain biological conditions: an adipocyte, a hepatocyte, and a "hybrid" adipocyte-like state of the hepatocyte. These phenotypes may also switch among each other, thus enabling phenotypic plasticity and consequently leading to simultaneous deregulation of the levels of molecules that maintain a hepatic identity and/or facilitate a partial or complete acquisition of adipocytic traits. These predicted trends are supported by the analysis of clinical data, further substantiating the putative role of phenotypic plasticity in driving NAFLD. Our results unravel how the emergent dynamics of underlying regulatory networks can promote phenotypic plasticity, thereby propelling the clinically observed changes in gene expression often associated with NAFLD.

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Genetics of Non-Alcoholic Fatty Liver and Cardiovascular Disease: Implications for Therapy?

Cited by 21 publications

References 85 publications

Nonalcoholic Fatty Liver Disease and Cardiovascular Disease: Overlapping Mechanisms

Nonalcoholic Fatty Liver Disease and Cardiovascular Disease: Overlapping Mechanisms

Genetic predisposition in metabolic‐dysfunction‐associated fatty liver disease and cardiovascular outcomes—Systematic review

Emergent properties of HNF4α-PPARγ network may drive consequent phenotypic plasticity in NAFLD

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