**1. Introduction**

Non-alcoholic fatty liver disease (NAFLD) has become the leading cause of chronic liver disease worldwide, with an estimated global prevalence of 25% among the adult population [1]. NAFLD comprises the full spectrum of the disease, from simple macrovesicular steatosis to non-alcoholic steatohepatitis (NASH), which is defined by the coexistence of steatosis, hepatocyte ballooning and inflammation with or without fibrosis, presenting an increased risk of progression to cirrhosis, hepatocellular carcinoma and end-stage liver disease [2]. In addition to the important clinical consequences derived from NAFLD, socioeconomic costs of this pathology have been reported to be enormous and the disease burden is expected to continue to increase in the coming years [3].

NAFLD is directly associated with the different components of the metabolic syndrome, including obesity, type 2 diabetes mellitus (T2DM), dyslipidemia and hypertension; in fact, obesity and insulin resistance/T2DM constitute the most common risk factors for NAFLD [4]. Actually, this disease is considered as the hepatic manifestation of the metabolic syndrome and bidirectional relationships between NAFLD and the rest of metabolic complications have been established [5]. Accordingly, environmental factors such as sedentary

**Citation:** Martínez-Montoro, J.I.; Cornejo-Pareja, I.; Gómez-Pérez, A.M.; Tinahones, F.J. Impact of Genetic Polymorphism on Response to Therapy in Non-Alcoholic Fatty Liver Disease. *Nutrients* **2021**, *13*, 4077.

https://doi.org/10.3390/nu13114077

Academic Editors: Daniel-Antonio de Luis Roman and Ana B. Crujeiras

Received: 16 September 2021 Accepted: 9 November 2021 Published: 15 November 2021

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**Copyright:** © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

lifestyle and high-caloric intake play a major part in NAFLD development and progression [6]. However, it is important to note that NAFLD pathogenesis is complex and several factors are involved in the natural history of this pathology. In line, novel environmental modifiers, such as gu<sup>t</sup> microbiota, have been proved to directly influence the course of the disease [7]. Importantly, genome-wide association studies (GWAS) and candidate gene studies have revealed, in the last few years, that NAFLD development, severity and risk of progression are strongly influenced by a number of single-nucleotide polymorphisms (SNPs), including patatin-like phospholipase domain-containing protein 3 (PNPLA3), transmembrane 6 superfamily member 2 (TM6SF2), membrane bound O-acyltransferase domain containing 7 (MBOAT7), glucokinase regulatory protein (GKRP) and hydroxysteroid 17-βdehydrogenase 13 (HSD17B13) as the main genetic determinants of NAFLD [8]. Moreover, the intricate interaction of genetic predisposition and environmental factors, such as nutrition, is considered to play a key role in the pathophysiology of NAFLD [9].

To date, the mainstay of treatment for NAFLD is weight loss [5]. Lifestyle intervention through dietary habits modifications and structured physical activity enables sustained weight loss and the subsequent hepatic fat content reduction and NASH improvement [10]. Importantly, the effect of specific training modalities, such as endurance training, may contribute to NASH improvement [11]. Furthermore, bariatric surgery (BS) has emerged as an effective therapeutic approach to NASH and fibrosis resolution [12]. However, a significant number of patients do not achieve the expected results even after adequate adherence to therapy. Thereby, among other factors, nutrient-gene interaction could explain this inter-individual variability in response to treatment and gene-based personalized therapies may constitute a useful tool in NAFLD treatment. In this article, we review the role of gene polymorphism in the variability in response to therapy in NAFLD, including the interaction between SNPs and dietary interventions, as well as the potential relationships among nutritional genomics, BS and other therapies.

### **2. Nutrigenetics and NAFLD Pathogenesis**

In addition to the classical metabolic risk factors for NASH and fibrosis progression, several studies have identified genetic associations with NAFLD susceptibility and severity [13]. The I148M (rs738409 C > G) variant of PNPLA3 (isoleucine to methionine exchange at the amino acid position 148 due to cytosine to guanine transversion in rs738409) is the most important risk mutation related to NAFLD, and it is strongly associated with the development and progression of the disease and also with the response to treatment [14] (Figure 1). PNPLA3 exhibits triacylglycerol lipase and acylglycerol transacylase activity in the hepatocytes and the I148M variant causes loss of function, promoting triglyceride accumulation in the hepatocytes [15]. The frequency of the I148M allele is particularly high in Hispanics (0.49), with lower frequencies in European Americans and African Americans; therefore, this fact may partially explain the differences in NAFLD prevalence among different ethnic groups [16]. On the other hand, TM6SF2 regulates hepatic lipid metabolism and the E165K missense variant impairs very low-density lipoprotein (VLDL) secretion and triggers hepatic lipid accumulation [17], whereas MBOAT7 rs641738 C > T SNP increases risk of NAFLD through the imbalance of phosphatidylinositol species [18]. GKRP rs780094 C > T variant presents a reduced capacity of glucokinase inhibition and consequently enhances glycolysis and glucose uptake by the liver [19]. Conversely, HSD17B13 rs6834314 A > G variant, involved in retinol metabolism, protects against NAFLD progression [20]. Finally, other reported genetic determinants associated with NAFLD include SH2B Adaptor Protein 1 (SH2B1), superoxide dismutase 2 (SOD2), signal transducer and activator of transcription 3 (STAT3), phosphatidylethanolamine-N–methyltransferase (PEMT), apolipoprotein B (APOB) or uncoupling protein 2 (UCP2) [21]. Of note, there are some mitochondria-related SNPs among the NAFLD-associated genetic determinants, since mitochondria dysfunction increases oxidative stress which is closely related to NAFLD pathogenesis [22]. Thus, C47T variant in the mitochondrial enzyme SOD2 is linked to advanced fibrosis in NASH [23], whereas mitochondrial UCP2-866 G > A polymorphism

reduces risk of NASH progression [24]. Furthermore, mitochondrial deoxyribonucleic acid (DNA) polymorphism 12361 A > G was associated with increased risk of moderate and severe NAFLD in a Chinese population [25].

**Figure 1.** The role of PNPLA3 rs738409C>G variant in NAFLD. PNPLA3 I148M is associated with NAFLD development and progression, and the interplay between this variant and environmental factors, including dietary habits, seems to be crucial in the pathophysiology of the disease. PNPLA3 I148M presence may also be related to an increased response to lifestyle interventions, bariatric surgery and certain types of therapeutic agents, such as the combination of sodium-glucose cotransporter 2 inhibitors and polyunsaturated fatty acid (PUFA). PNPL3: patatin-like phospholipase domain-containing protein 3; I148M (rs738409 C > G): isoleucine to methionine exchange at the amino acid position 148 due to cytosine to guanine transversion in rs738409); NAFLD: non-alcoholic fatty liver disease.

Notably, SNP-mediated liver damage only explains a small proportion of NAFLD pathophysiology, and synergistic interaction between these risks variants and the environment are needed to trigger significant alterations [26]. As an example, Smagris et al., showed that PNPLA3 I148M knock in mice developed sucrose diet-dependent hepatic steatosis, but no hepatic alterations were found in chow-fed animals with the mutation [27]. Moreover, a preclinical study revealed that several mitochondrial gene polymorphisms only predisposed to NASH when either a methionine and choline deficient diet or Westernstyle diet was administrated [28]. Thus, the interaction between nutrients and genetic factors could modulate NAFLD presence and evolution. Additionally, it is also important to bear in mind that nutrition can also give rise to modifications in gene expression through several epigenetic mechanisms, including histone modification, DNA methylation and the regulation of transcription by micro-ribonucleic acids (miRNAs) [29]. These complex pathways are encompassed within the field of nutrigenomics, which constitutes a key element in NAFLD pathogenesis [29]. However, this topic is beyond the scope of this review and we will focus on the influential effect of genetics on response to different nutrients in NAFLD.
