Dec 01, 2023
Non-alcoholic fatty liver disease (NAFLD) is linked to obesity, insulin resistance and metabolic syndromes such as type 2 diabetes mellitus (T2DM), hypertension and dyslipidemia. NAFLD increases in prevalence with obesity burden and has emerged as the leading cause of chronic liver disease in the world. NAFLD causes simple steatosis or a potentially progressive inflammatory form (non-alcoholic steatohepatitis-NASH), leading to fibrosis and ultimately cirrhosis and/or hepatocellular cancer (HCC). The mechanisms of NAFLD development are quite complex and multiple environmental and genetic factors are involved. In this context, the main association uncovered concerns the Patatin-like phospholipase domain-containing 3 (PNPLA3) rs738409 single nucleotide polymorphism (SNP), which has also been shown to interact with the environment. Since a specific pharmacological approach has not yet been approved therapeutically, calorie diets and physical activity recommendations have been used to lose weight so far. The development of NAFLD has been associated with high weight, excess calorie intake, refined carbohydrate consumption, and saturated fat. Precision nutrition is a treatment approach that creates nutritional styles by taking into account the genetic and epigenetic information of individuals, as well as their gender, age and pathophysiological conditions. If a variant predisposing to NASH is identified, this approach allows targeting the same gene or molecular pathway that harbors the variant to reverse or halt inflammation, fibrosis, and hepatic steatosis.
Patatin-like phospholipase domain-containing 3 (PNPLA3) rs738409 SNP is one of the major genetic determinants of non-alcoholic fatty liver disease (NAFLD) and is strongly regulated by changes in energy balance dietary factors.
In the study conducted by Campo et al., the effect of the interaction between the PNPLA3 rs738409 genotype and dietary components on the risk of NAFLD was examined in 181 NAFLD patients, 60.2% of whom were male, with an average age of 53 (44-62) at the University Hospital of Turin. Controlled Attenuation Parameter (CAP) was used as the evaluation criterion. A CAP value ≥ 300 dB/m was used to define severe steatosis (S3).An independent group of 46 biopsy-proven NAFLD subjects was used as the validation cohort. Most of the cases (56.3%) had S3 (Steatosis) and showed increased liver stiffness, AST and ALT levels compared to those with CAP <300 dB/m. In logistic regression analyses, the interaction between carbohydrate intake and PNPLA3 G risk allele carriers was found to be significantly associated with S3 (p=0.001). The same result was confirmed in the validation cohort, where the interaction between high carbohydrate intake (≥48%) and the PNPLA3 SNP was significantly associated with steatosis ≥33% (p=0.038). Conclusion In NAFLD patients carrying the CG/GG allele of PNPLA3 rs738409, carbohydrate intake greater than or equal to 48% may increase the risk of significant steatosis.
**Exclusion criteria included alcohol consumption of more than 21/14 units/week on average in the previous 6 months or a history of excessive alcohol consumption in the last 5 years.
Results of the Study
PNPL43 rs738409 genotype was CC in 64 (35.4%) patients, CG in 86 (47.5%) patients, and GG in 31 (17.1%) patients. For the purpose of the analysis, participants were divided into those with mild or moderate steatosis (CAP 300 dB/m, n=79) and those with severe steatosis (CAP≥300 dB/m, n = 102). However, patients with severe fatty liver had a higher rate of diabetes, higher BMI, as well as increased AST, ALT, glucose and triglyceride levels. PNPLA3 G allele (68.6%) and liver stiffness were significantly increased in patients with CAP≥300 compared to the mild or moderate steatosis group.
The risk of fatty liver disease was evaluated according to the interaction of genetics and dietary intake. After adjusting for age, protein, carbohydrate, energy intake and the presence of diabetes, a significant interaction was found between risk genotype CG or GG carriers of the PNPLA3 genetic variant and carbohydrate intake, high carbohydrate intake (≥48%). has been shown to be associated with an increased risk of severe hepatic steatosis (≥300 dB/m). In particular, the risk of developing hepatic steatosis is higher in individuals with carbohydrate intake ≥48% and carriers of the PNPLA3 CG or GG risk allele with the wild-type CC genotype than in PNPLA3 carriers with the same amount of carbohydrates. is high. In another study, it was observed that triglyceride hydrolyzing capacity in the liver decreased in PNPLA3 GG carrier Spanish children, and liver fat increased when Kh intake increased. Mutant allele downregulation of the PNPLA3 gene showed improvement in NAFLD (Linden et al., 2019). According to the data obtained from the study, it is very important to establish or change the nutritional style according to genetic analysis. In individuals carrying the G allele in the PNPLA3 gene, the share of carbohydrates in the entire energy intake should be below 48%, thus providing relative protection against fatty liver, fibrosis and steatosis.
REFERENCES
Lindén D, Ahnmark A,Pingitore P,Ciociola E,Ahlstedt I,Andréasson AC et al.(2019). Pnpla3 silencing with antisense oligonucleotides ameliorates nonalcoholic steatohepatitis and fibrosis in Pnpla3 I148M knock-in mice. Mol Metabol.; 22: 49-61https://doi.org/10.1016/J.MOLMET.2019.01.013
Campo NPD, Dileo E, Castelnuovo G, Rosso C, A Armandi, E Bugianesi. (2023). A nutrigenetic precision approach for the management of non-alcoholic fatty liver disease. Clinical Nutrition; 42, 2181-2187. DOI:https://doi.org/10.1016/j.clnu.2023.09.022