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Archives of Clinical Toxicology

ISSN: 2692-8280

Review Article Open Access
Volume 6 | Issue 1 | DOI: https://doi.org/10.46439/toxicology.6.030

Non-alcoholic fatty liver disease: Genetic susceptibility

Shakil A Saghir, M.Sc., M.S.P.H., Ph.D., DABT, ERT, Fellow ATS, Fellow RSB1,2,3, Nicole Shams4, Lianette Veliz4, Saleh Alfuraih4,5, Yadollah Omidi4, Jaleh Barar4, Ajay Sharma6, Rais Ansari, Ph.D.4,*
  • 1ToxInternational Inc., Hilliard, OH, USA
  • 2Department of Biological & Biomedical Sciences, Aga Khan University, Karachi, Pakistan
  • 3Institute of Environmental Science and Meteorology, University of the Philippines-Diliman, Quezon City, Philippines
  • 4Department of Pharmaceutical Sciences, Barry and Judy Silverman College of Pharmacy, Health Professions Division, Nova Southeastern University, Fort Lauderdale, FL, USA
  • 5Department of Pharmacology and Toxicology, Faculty of Pharmacy, Northern Border University, Rafha, Saudi Arabia
  • 6Department of Biomedical and Pharmaceutical Sciences, Chapman University School of Pharmacy, Chapman University, Irvine, CA, USA
+ Affiliations - Affiliations

Corresponding Author

Rais Ansari, ra557@nova.edu

Received Date: May 22, 2024

Accepted Date: June 05, 2024

Citation:

Saghir SA, Shams N, Veliz L, Alfuraih S, Omidi Y, Barar J, et al. Non-alcoholic fatty liver disease: Genetic susceptibility. Arch Clin Toxicol. 2024;6(1):33-47.


Copyright: © 2024 Saghir SA, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

The prevalence of Non-alcoholic Fatty Liver Disease (NAFLD) is increasing, particularly in individuals who consume minimal to no alcohol. Currently, NAFLD affects at least 32% of the global population. Although not all but approximately 5-10% cases of NAFLD progress to non-alcoholic steatohepatitis (NASH), a condition arising from lipotoxicity. Patients with NASH may further develop liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). However, it is important to note that progression from NAFLD to NASH and HCC is not inevitable for all patients. The pathogenesis of HCC in the context of NAFLD and NASH remains poorly understood, however, fat accumulation, often due to obesity or metabolic syndrome, leads to lipotoxicity. In individuals with type 2 diabetes (T2D), elevated insulin levels promote lipolysis in adipose tissue and activate lipid-synthesizing enzymes such as fatty acid synthase (FAS) and stearoyl-CoA desaturase 1 (SCD1), which contribute to lipid accumulation in the liver. Additionally, high glucose levels in T2D can alter gene regulation by activating carbohydrate response-element binding protein (ChREBP) and insulin can increase the activity of sterol regulatory element binding protein (SREBP-1c). These lipogenic transcription factors are known to directly or indirectly activate patatin-like phospholipase domain-containing protein 3 (PNPLA3). Recent research has found elevated levels of angiotensinogen (AGT) and des-angiotensin in both experimental animals and patients with NAFLD. Emerging evidence highlights the significance of genetic factors in the risk of developing NAFLD. Here we explore the association between specific genes and hepatosteatosis, detailing the roles of T2D and obesity in the progression from NAFLD to NASH, and involvement of hepatic stellate cells in liver fibrosis. Additionally, we examine the impact of genes such as PNPLA3, MBOAT7, TM6SF2, GKRP, CCN3, and AGT as well as role of single nucleotide polymorphisms in gene regulation and their contribution to the risk of NAFLD.

Keywords

Hepatosteatosis, Non-alcoholic fatty liver disease, Non-alcoholic steatohepatitis, Obesity, Type 2 diabetes mellitus

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