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. 2024;6(1):21-32.
doi: 10.46439/toxicology.6.029.

Non-alcoholic fatty liver disease: Role of PNPLA3 and its association with environmental chemicals

Shakil A Saghir  1   2   3 , Ata Abbas  4 , Saleh Alfuraih  5   6 , Ajay Sharma  7 , Jean Latimer  6   8 , Yadollah Omidi  6 , Rais Ansari  6
Affiliations

Non-alcoholic fatty liver disease: Role of PNPLA3 and its association with environmental chemicals

Shakil A Saghir et al. Arch Clin Toxicol (Middlet). 2024.

Abstract

Globally, non-alcoholic fatty liver disease (NAFLD) is on the rise with 30-32%, 27-33%, 35-48%, 36%, 9-20%, and 36-38% prevalence in Asia, Europe, North America, South America, Africa, and Australia, respectively. Approximately, 5-10% of NAFLD proceeds to hepatitis called non-alcoholic steatohepatitis (NASH). NASH often progresses to liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). Precise mechanism(s) for the development of HCC is not fully understood in NAFLD and NASH patients. Higher insulin levels in type 2 diabetes (T2D) can result in lipolysis of adipose tissue activating lipid synthesizing enzymes such as fatty acid synthase and stearoyl-CoA desaturase-1, resulting in lipid accumulation in liver. Higher levels of glucose in T2D patients activate carbohydrate response element binding protein and insulin which increases the level of active sterol regulatory element binding protein. These lipogenic transcription factors activate patatin-like phospholipase domain-containing protein-3 (PNPLA3) from their response elements in the promoter. Endocrine disrupting chemicals (EDCs) and persistent organic pollutants (POPs) are implicated in T2D development and NAFLD. The emerging association between POPs, including insecticides, fungicides, herbicides, and diabetes has been noted. However, their connection with NAFLD remains less evident. Here, we reviewed association of POPs, especially EDCs, and role of PNPLA3 in the development of NAFLD and NASH. We also reviewed the role of single nucleotide polymorphisms of PNPLA3's association with NAFLD.

Keywords: Hepatocellular carcinoma; Liver fibrosis; Non-alcoholic fatty liver disease; Non-alcoholic steatohepatitis; Patatin-like phospholipase domain-containing protein 3.

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Figures

Figure 1.
Figure 1.
The conditions and transformation of normal liver to NAFLD, and NASH.
Figure 2.
Figure 2.
Regulation of the PNPLA3 gene by carbohydrate-response element binding protein (ChREBP) and sterol regulatory element binding protein-1c (SREBP-1c).
See this image and copyright information in PMC

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