NAFLD in the 21st Century: Current Knowledge Regarding Its Pathogenesis, Diagnosis and Therapeutics

Abstract

Non-alcoholic fatty liver disease (NAFLD) is a major public health issue worldwide. It is the most common liver disease in Western countries, andits global prevalence is estimated to be up to 35%. However, its diagnosis may be elusive, because liver biopsy is relatively rarely performed and usually only in advanced stages of the disease. Therefore, several non-invasive scores may be applied to more easily diagnose and monitor NAFLD. In this review, we discuss the various biomarkers and imaging scores that could be useful in diagnosing and managing NAFLD. Despite the fact that general measures, such as abstinence from alcohol and modulation of other cardiovascular disease risk factors, should be applied, the mainstay of prevention and management is weight loss. Bariatric surgery may be suggested as a means to confront NAFLD. In addition, pharmacological treatment with GLP-1 analogues or the GIP agonist tirzepatide may be advisable. In this review, we focus on the utility of GLP-1 analogues and GIP agonists in lowering body weight, their pharmaceutical potential, and their safety profile, as already evidenced inanimal and human studies. We also elaborate on other options, such as the use of vitamin E, probiotics, especially next-generation probiotics, and prebiotics in this context. Finally, we explore future perspectives regarding the administration of GLP-1 analogues, GIP agonists, and probiotics/prebiotics as a means to prevent and combat NAFLD. The newest drugs pegozafermin and resmetiron, which seem to be very promising, arealso discussed.

Keywords: GLP-1 analogues; NAFLD; pegozafermin; prebiotics; probiotics; resmetiron; tirzepatide.

Figure 1

Legend: Excess fat accumulation in the liver may lead to the production of lipotoxic species, which induce ER stress and mitochondrial dysfunction. In particular, the ER is implicated in protein maturation. Excess lipid formation exceeds the ER’s capacity to produce mature proteins; thereby, unfolded proteins accumulate. This increase in unfolded proteins activates a cascade known as the UPR. Chronic ER stress may induce the UPR cascade, which, in turn, may lead to severe inflammation, the production of ROS, and ultimately, cell death.

Figure 2

Legend: ROS binds to NLRP3, an inflammasome that, when activated by the canonical inflammasome pathway, i.e., via pro-caspase-1, results in the production of caspase-1. Caspase-1 leads to transformational alterations in NLRP3, which provoke the production of the pro-inflammatory cytokines IL-18 and IL-1β. This vicious cycle accounts for the inflammation seen in NASH. In addition, collagen deposition, which is mainly due to the activation of TGF-βresults in fibrosis seen in NAFLD.

Figure 3

Legend: Literally, PNPLA3, TM6SF2, GCKR and MBOAT7 are major genes associated with NAFLD. More specifically, GWAS have demonstrated that SNPs in the above-mentioned genes have been related to NAFLD development.