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

## TL;DR

This paper reviews how the PNPLA3 gene and environmental chemicals may contribute to non-alcoholic fatty liver disease and its progression.

## Contribution

The paper provides a review linking persistent organic pollutants, endocrine disruptors, and PNPLA3 gene variants to NAFLD and NASH.

## Key findings

- PNPLA3 is activated by lipogenic transcription factors in type 2 diabetes, contributing to liver lipid accumulation.
- Persistent organic pollutants and endocrine disrupting chemicals are linked to NAFLD and T2D development.
- Single nucleotide polymorphisms in PNPLA3 are associated with non-alcoholic fatty liver disease progression.

## 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.