The Role of Insulin Resistance in Fueling NAFLD Pathogenesis: From Molecular Mechanisms to Clinical Implications

Abstract

Non-alcoholic fatty liver disease (NAFLD) represents a predominant hepatopathy that is rapidly becoming the most common cause of hepatocellular carcinoma worldwide. The close association with metabolic syndrome's extrahepatic components has suggested the nature of the systemic metabolic-related disorder based on the interplay between genetic, nutritional, and environmental factors, creating a complex network of yet-unclarified pathogenetic mechanisms in which the role of insulin resistance (IR) could be crucial. This review detailed the clinical and pathogenetic evidence involved in the NAFLD-IR relationship, presenting both the classic and more innovative models. In particular, we focused on the reciprocal effects of IR, oxidative stress, and systemic inflammation on insulin-sensitivity disruption in critical regions such as the hepatic and the adipose tissue, while considering the impact of genetics/epigenetics on the regulation of IR mechanisms as well as nutrients on specific insulin-related gene expression (nutrigenetics and nutrigenomics). In addition, we discussed the emerging capability of the gut microbiota to interfere with physiological signaling of the hormonal pathways responsible for maintaining metabolic homeostasis and by inducing an abnormal activation of the immune system. The translation of these novel findings into clinical practice could promote the expansion of accurate diagnostic/prognostic stratification tools and tailored pharmacological approaches.

Keywords: insulin resistance; non-alcoholic fatty liver disease; precision medicine.

Figure 1

Overview of molecular mechanisms underlying worsening NAFLD pathogenesis and IR. The insulin-signaling cascade is abolished in the Akt/FoxO1 pathway (dashed red arrow), but not in the mTORC1/SREBP-1c pathway (solid red arrow). The LPS-TLR4 interaction culminates in the activation of PKCθ, which mediates the proteasomal degradation of IRS1/2 and PP2A, which inhibits Akt further downstream in the insulin cascade (green arrow). The release of cytokines, such as IL-6 and TNF-α, from Kupffer cells results in the activation, following the interaction with their own receptors, of the JAKs/STAT3 (purple arrow) and JNK/NF-κB (yellow arrow) pathways, respectively. The latter both culminate in the activation of SOCS, which is responsible for inhibiting IRS1/2. The diacylglycerol (DAG) activates PKCε, which inhibits the tyrosine kinase activity of the insulin receptor (black arrow). Up arrows (↑) stand for enhanced expression (in the case of a gene), production (in the case of mediators), and occurrence (in the case of the relative pathological event).

Figure 2

Dimorphism of the sex hormones estrogens and testosterone in the liver of the two sexes. Estrogens display a similar role in both sexes, interacting with their receptors (ERα) in plasma membrane of liver cells, which, once activated, migrate in the nucleus and bind to estrogen-responsive element (ERE) on their target genes. Estrogens suppress hepatic glucose production (HGP) by inhibiting the expression of FOXO1. Estrogens also impair the hepatic de novo lipogenesis (DNL) by reducing the expression of genes such as SREBP-1C, FASN, and SCD1, and promote fatty-acid oxidation (FAO). Overall, in physiologic conditions, estrogens play a significant role in the modulation of glucose equilibrium in the liver of both sexes (A,B). In contrast, androgens, especially testosterone, show different functions in the liver of the two sexes through the interaction with their membrane receptors AR. In male livers, an increase in testosterone levels has beneficial effects in reducing glucose uptake, by inhibiting the transcription of GLUT-2. It has an important action also in the reduction in DNL in male livers, acting in the suppression of the transcription of SREBP-1C and PPARγ and in the inhibition of HGP through FOXO1 (A). Differently, in female livers, altered levels of testosterone promote an increase in hepatic steatosis by impairing hepatic glucose metabolism, thus predisposing females to insulin resistance (B). Up arrows (↑) and down arrows (↓) indicate, respectively, enhanced and reduced expression (in the case of a gene), production (in the case of mediators), and occurrence (in the case of the relative pathological event).

Figure 3

Principal mechanisms of action of therapies currently undergoing clinical studies for ameliorating IR-related hepatic steatosis. AMPK: AMP-activated protein kinase; ChREBP: Carbohydrate Response Element Binding Protein; FXR: Farnesoid X receptor; FFAs: Free Fatty Acids; IR: Insulin resistance; OCA: obeticholic acid; PPAR: Peroxisome proliferator-activated receptor; SGLT2: Sodium-glucose transporter 2; and SREBP-1: Sterol regulatory element-binding protein 1.