Exploring the role of genetic variations in NAFLD: implications for disease pathogenesis and precision medicine approaches

Abstract

Non-alcoholic fatty liver disease (NAFLD) is one of the leading causes of chronic liver diseases, affecting more than one-quarter of people worldwide. Hepatic steatosis can progress to more severe forms of NAFLD, including NASH and cirrhosis. It also may develop secondary diseases such as diabetes and cardiovascular disease. Genetic and environmental factors regulate NAFLD incidence and progression, making it a complex disease. The contribution of various environmental risk factors, such as type 2 diabetes, obesity, hyperlipidemia, diet, and sedentary lifestyle, to the exacerbation of liver injury is highly understood. Nevertheless, the underlying mechanisms of genetic variations in the NAFLD occurrence or its deterioration still need to be clarified. Hence, understanding the genetic susceptibility to NAFLD is essential for controlling the course of the disease. The current review discusses genetics' role in the pathological pathways of NAFLD, including lipid and glucose metabolism, insulin resistance, cellular stresses, and immune responses. Additionally, it explains the role of the genetic components in the induction and progression of NAFLD in lean individuals. Finally, it highlights the utility of genetic knowledge in precision medicine for the early diagnosis and treatment of NAFLD patients.

Keywords: Gene variants; Lean NAFLD; NAFLD; NASH; Polymorphism; Precision medicine.

Fig. 1

Schematic diagram of lipid metabolism in NAFLD. The uptake of circulating fatty acids from chylomicron remnants or adipose tissue by FATP2/5 and CD36 leads to lipid accumulation in the liver. Fatty acid can take part in several pathways and transferred to the mitochondria and participate in β-oxidation (A). ACSL converts fatty acids to FA-CoA, which then enters the TAG synthesis pathway via chain reactions catalyzed by GPAT, AGPAT, PAP, and DGAT (B). Produced TAGs can be stored as LDs. PNPLA3, MBOAT7, and HSD17B13 are located on the surface of lipid droplets in hepatocytes. PNPLA3 catalyzes the hydrolysis of TG, MBOAT7 plays an important role during the noncanonical hepatic triglyceride synthesis pathway, and HSD17B13 appears to be involved in hepatic lipid biogenesis and metabolism (C). At the ER, TAGs can also be packaged into VLDL by MTTP and ApoB. TM6SF2 is also located in the ER and regulates VLDL secretion. Nascent VLDL particles packaged into VLDL transport vesicles are transported from the ER to the Golgi apparatus, and Apoc3, a component of VLDL, stimulates VLDL assembly and secretion. Finally, mature VLDLs are secreted through vesicle-mediated exocytosis (D)

Fig. 2

Schematic representation of the glucose–insulin signaling pathway. Binding of insulin to its receptor (IR) stimulates activation of downstream PI3K/Akt cascade. Activation of Akt by insulin results in glycogen synthesis and gluconeogenesis through GSK3 and FoxO1, respectively. ENPP1 interacts with Insulin receptor and inhibits its kinase activity. The GCK phosphorylates glucose in the hepatocyte to G6P and allows glucose to enter the cell. During glycolysis which is regulated by GCKR through inhibiting GCK, pyruvate is generated and transported to the mitochondria where it is decarboxylated to acetyl-CoA leading to de novo lipogenesis. The activity of SREBP1c is upregulated by insulin signaling, whereas ChREBP has been identified as a glucose-activated transcription factor, both of which contribute to de novo lipogenesis and fatty acid synthesis. During DNL, the ACC enzyme converts acetyl-CoA to malonyl-CoA, and then the FASN enzyme produces SFAs. Additionally, SCD1 transforms SFAs into MUFA, which is used as a substrate for the production of fatty acids. FOXO1 Forkhead box protein O1, PI3K phosphatidyl inositol 3-kinase, AKT AKT serine/threonine kinase 1, GS glycogen synthase, G6P glucose-6-phosphate, GCK glucokinase, GCKR glucokinase regulator, ChREBP carbohydrate-response element-binding protein, SREBP1 sterol regulatory element-binding protein 1, FASN fatty acid synthase, SCD1 stearoyl-coa desaturase 1, MUFA monounsaturated fatty acids, SFA saturated fatty acid, ACC acetyl-CoA carboxylase

Fig. 3

Schematic representation of cellular stresses in NAFLD. ER stress increases lipid droplet accumulation by activating factors involved in lipogenesis. IRGM plays an important role in increasing lipophagy of LDs. IRGM promotes lipophagy through complex formation with ULK1 and Beclin, binding to ATG16L1, and stimulation by Sirt1. Moreover, enhanced FFA β-oxidation in mitochondria by production of large amounts of ROS leads to a disruption of the electron transport chain. This defect leads to the leakage of e-, which immediately combines with oxygen to generate the superoxide anion radical, which is then converted to H₂O₂ by SOD2 activity. The antioxidant enzymes GPX1 and catalase convert H₂O₂ into H₂O and O₂. On the other hand, ER stress leads to mitochondrial damage by causing oxidative stress. IRGM regulates mitofilin stability during mitochondrial depolarization, leading to PINK1-Parkin-dependent ubiquitination and removal of defective mitochondria

Fig. 4

Schematic representation of the relationship between inflammation and NASH disease progression. Upon stimulation with TNF-α, the NF-κB pathway is activated, as indicated by phosphorylation and nuclear translocation of NF-κB and transcription of its target genes, including IL-6 and IL-1β. Newly synthesized IL-6 is secreted by cells and binds to the IL-6R in an autocrine or paracrine manner, leading to activation of the IL-6R/gp130 complex and intracellular JAK1/2 kinases. STAT3 proteins are then phosphorylated by JAK1/2, dimerize, enter the nucleus, and initiate transcription of STAT3-dependent genes such as TGF-β, IL-6, IL-17, and IL-1β, which contribute to the development of inflammatory responses Alternatively, the first signal for NLRP3 inflammasome activation is NF-κB-mediated NLRP3 transcription. When activated, the NLRP3 inflammasome converts caspase-1, pro-IL-18, and pro-IL-1β into active forms, triggering an inflammatory response. IL-6R interleukin-6 receptor, gp130 glycoprotein 130