Genetic risk factors associated with NAFLD

Kim, Dong Yun; Park, Jun Yong

doi:10.20517/2394-5079.2020.96

Cited by 12 publications

(13 citation statements)

References 64 publications

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“…Last but not least, the accurate assessment of NAFLDassociated genetic/epigenetic risk factors of diseases and likelihood of disease progression is going to aid to target individualized appropriate treatments (163).…”

Section: Discussionmentioning

confidence: 99%

Oxidative Stress in Non-alcoholic Fatty Liver Disease. An Updated Mini Review

et al. 2021

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Non-alcoholic fatty liver disease (NAFLD) is a challenging disease caused by multiple factors, which may partly explain why it remains still orphan of an adequate therapeutic strategy. Herein we focus on the interplay between oxidative stress (OS) and the other causal pathogenetic factors. Different reactive oxygen species (ROS) generators contribute to NAFLD inflammatory and fibrotic progression, which is quite strictly linked to the lipotoxic liver injury from fatty acids and/or a wide variety of their biologically active metabolites in the context of either a two-hit or a (more recent) multiple parallel hits theory. An antioxidant defense system is usually able to protect hepatic cells from damaging effects caused by ROS, including those produced into the gastrointestinal tract, i.e., by-products generated by usual cellular metabolic processes, normal or dysbiotic microbiota, and/or diet through an enhanced gut–liver axis. Oxidative stress originating from the imbalance between ROS generation and antioxidant defenses is under the influence of individual genetic and epigenetic factors as well. Healthy diet and physical activity have been shown to be effective on NAFLD also with antioxidant mechanisms, but compliance to these lifestyles is very low. Among several considered antioxidants, vitamin E has been particularly studied; however, data are still contradictory. Some studies with natural polyphenols proposed for NAFLD prevention and treatment are encouraging. Probiotics, prebiotics, diet, or fecal microbiota transplantation represent new therapeutic approaches targeting the gut microbiota dysbiosis. In the near future, precision medicine taking into consideration genetic or environmental epigenetic risk factors will likely assist in further selecting the treatment that could work best for a specific patient.

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Section: Discussionmentioning

confidence: 99%

Oxidative Stress in Non-alcoholic Fatty Liver Disease. An Updated Mini Review

et al. 2021

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“…NAFLD is a multisystem disease that not only results in progressive liver disease but also affects extrahepatic organs [ 21 ]. Various demographic [ 6 – 9 ], clinical [ 10 ], and genetic factors [ 11 ] showed association with the risk of NAFLD. Among genetic risk factors, PNPLA3 rs738409 polymorphism demonstrated significant association with NAFLD.…”

Section: Discussionmentioning

confidence: 99%

“…Age [ 6 , 7 ], gender [ 6 – 8 ], ethnicity [ 9 ], metabolic syndrome (MetS), and its components including dyslipidemia, obesity, hypertension (HTN), and T2DM [ 10 ] were associated with the risk of NAFLD. Genetic factors such as the patatin-like phospholipase domain containing 3 ( PNPLA3 ), the transmembrane 6 superfamily member 2 ( TM6SF2 ), the membrane-bound O -acyltransferase domain containing 7 ( MBOAT7 ), and the glucokinase regulator ( GCKR ) [ 11 ] were also associated with the risk of NAFLD. The product of human PNPLA3 gene, i.e., triacylglycerol lipase enzyme mediates hydrolysis of triacylglycerol (TAG) in adipocytes.…”

Section: Introductionmentioning

confidence: 99%

Sociodemographic and genetic determinants of nonalcoholic fatty liver disease in type 2 diabetes mellitus patients

Adnan

Wajid

Noor

et al. 2022

Journal of Genetic Engineering and Biotechnology

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Background Nonalcoholic fatty liver disease (NAFLD) showed significant association with PNPLA3 rs738409 polymorphism in unrelated individuals. However, it is still unknown whether the relationship of NAFLD with PNPLA3 variant exists or not among subjects with type 2 diabetes mellitus (T2DM). Therefore, the study aimed to evaluate sociodemographic and genetic determinants of NAFLD in type 2 diabetics. Methods The cross-sectional analytical study was conducted at the Department of Molecular Biology, Virtual University of Pakistan, Lahore, Pakistan, during 2019–2020. A total of 153 known cases of T2DM were enrolled using convenience sampling. After excluding patients (n = 24) with HCV, alcoholism, or missing information, data from 129 eligible diabetics with and without NAFLD were analyzed using SPSS. Odds ratios using crosstabs and adjusted odds ratios using binary and multinomial logistic regression were calculated to measure the risk of NAFLD. Results Adults 18–35 years were 7.0%, 36–55 years were 64.3%, ≥ 56 years were 28.7%, and females were 66.7%. A total of 41.1% of patients had obesity, 52.7% had NAFLD, and 29.05% carried mutant G allele of rs738409 polymorphism. Among overall diabetics, NAFLD showed association with female (OR = 2.998, p = 0.007), illiterate (OR = 3.067, p = 0.005), and obese (OR = 2.211, p = 0.046) but not with PNPLA3 genotype under any model (all p = > 0.05). Among obese diabetics, NAFLD showed association with female (AOR = 4.010, p = 0.029), illiterate (AOR = 3.506, p = 0.037), GG + CG/CC (AOR = 3.303, p = 0.033), and GG/CG + CC (AOR = 4.547, p = 0.034) using binary regression and with female (AOR = 3.411, p = 0.051), illiterate (AOR = 3.323, p = 0.048), GG + CG/CC (AOR = 3.270, p = 0.029), and GG/CG + CC (AOR = 4.534, p = 0.024) using multinomial regression. Conclusions NAFLD and obesity were the most common comorbid diseases of T2DM. Gender female, being illiterate, and PNPLA3 rs738409 polymorphism were significant risk factors of NAFLD among obese diabetic patients.

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“…Scientific evidence suggests that genetic factors strongly influence the development of MAFLD, and these factors overlap with those identified as factors for NAFLD and NASH (non-alcoholic steatohepatitis) ( 1 , 5 , 8 ). The patatin-like phospholipase domain-containing protein 3 gene ( PNPLA3 ), Membrane bound O-acyltransferase domain containing 7 gene ( MBOAT7 ), transmembrane 6 superfamily member 2 gene ( TM6SF2 ), and glucokinase regulator gene ( GCKR ) have been the most recognized genes involved in the pathogenesis of fatty liver diseases ( 9 , 10 ). PNPLA3 was the first NAFLD-related genetic variant (rs738409; I148M) identified that displays a robust association with the development and severity of NAFLD.…”

Section: Pathophysiological Processes In the Development Of Mafldmentioning

confidence: 99%

“…PNPLA3 was the first NAFLD-related genetic variant (rs738409; I148M) identified that displays a robust association with the development and severity of NAFLD. This gene is highly expressed in the liver and white adipose tissues and is regulated by insulin signaling via LXR and sterol regulatory binding protein 1c (SREBP1c) pathways ( 5 , 9 , 11 , 12 ). Normally, this protein hydrolyzes triglycerides and retinyl esters, however the genetic variant results in impairment of the hydrolase activity, leading to hepatic lipid accumulation.…”

Section: Pathophysiological Processes In the Development Of Mafldmentioning

confidence: 99%

Development of LXR inverse agonists to treat MAFLD, NASH, and other metabolic diseases

Griffett

Burris

2023

Front. Med.

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Activation of LXR activity by synthetic agonists has been the focus of many drug discovery efforts with a focus on treatment of dyslipidemia and atherosclerosis. Many agonists have been developed, but all have been hindered due to their ability to efficaciously stimulate de novo lipogenesis. Here, we review the development of LXR inverse agonists that were originally optimized for their ability to enable recruitment of corepressors leading to silencing of genes that drive de novo lipogenesis. Such compounds have efficacy in animal models of MAFLD, dyslipidemia, and cancer. Several classes of LXR inverse agonists have been identified and one is now in clinical trials for treatment of severe dyslipidemia.

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Genetic risk factors associated with NAFLD

Cited by 12 publications

References 64 publications

Oxidative Stress in Non-alcoholic Fatty Liver Disease. An Updated Mini Review

Oxidative Stress in Non-alcoholic Fatty Liver Disease. An Updated Mini Review

Sociodemographic and genetic determinants of nonalcoholic fatty liver disease in type 2 diabetes mellitus patients

Development of LXR inverse agonists to treat MAFLD, NASH, and other metabolic diseases

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