The prevalence of non-alcoholic fatty liver disease (NAFLD) is becoming prevalent worldwide and is characterized by excessive fat accumulation in the liver. It is observed to occur with metabolic disorders, including type 2 diabetes (T2D), obesity, and cardiovascular disease. Mounting evidences suggest that the presence of NAFLD increases the incidence of type 2 diabetes, while diabetes in NAFLD progresses to more severe forms of steatohepatitis, cirrhosis, and hepatocellular carcinoma.

The development of NAFLD in the absence of glucose metabolism disorders was found to be correlated with overexpression of diacylglycerol acyltransferase 2 (DGAT2), an enzyme catalyzing the final step of hepatic triglyceride biosynthesis from diacylglycerol (DAG) in an experimental animals. Similarly, it was observed that NAFLD-related hepatic insulin resistance in humans is due to an increase in hepatic DAG content. Therefore, DGAT2 gain-of-function gene variants are correlated with an increased risk of NAFLD with disproportionately conserved insulin sensitivity in humans. Certain animal studies also supports that that inhibiting secretion of VLDL from the liver by genetic modification also causes liver steatosis with conserved insulin sensitivity. Recent advances in genome-wide association studies (GWAS) have recognized several gene variants such as patatin-like phospholipase domain-containing 3 (PNPLA3), transmembrane 6 superfamily member 2 protein (TM6SF2), and MBOAT7 that play a role in the development of NAFLD in patients with normal body mass index and a few features of metabolic syndromes.  Among these, PNPLA3 gene variant is the first and strongest common variant that is associated with NAFLD. Some studies demonstrated that PNPLA3 rs738409 GG gene variant carriers have 73% more liver fat, a 3.2-fold higher risk of liver necro-inflammation, and a 1.9-fold higher risk of cirrhosis than PNPLA3 wild-type CC genotype carriers. The PNPLA3 rs738409 C > G variant offers a disproportionate progression of NAFLD and diabetes. The expression of PNPLA3 is regulated by the insulin-regulated transcription factor sterol regulatory element-binding protein-1c (SREBP-1c), and pathogenic PNPLA3 mutant products deposits and results in obesity and insulin resistance, thus worsening liver steatosis, inflammation, and cirrhosis.

As NAFLD and T2D share common pathophysiology, i.e. insulin resistance and coexist with each other, so therapeutic approaches target insulin resistance demonstrate efficacy in treating NAFLD. This includes various pharmacological therapies as well as several specific gene targeted therapy for patients with NAFLD with a relative conservation of glucose metabolism. Numerous clinical trials have suggested that NAFLD patients with specific gene variants has different response to lifestyle and drug intervention. Although various clinical trials are undergoing to estimate the response among the NAFLD patients with different gene variants in comparison to other NAFLD interventions, more evidence is required that can provide a personalized treatment based on genetic classification.

Source: Front Pharmacol. 2019;10:877