Pathophysiological Mechanisms in Non-Alcoholic Fatty Liver Disease: From Drivers to Targets

Abstract

Non-alcoholic fatty liver disease (NAFLD) is characterized by the excessive and detrimental accumulation of liver fat as a result of high-caloric intake and/or cellular and molecular abnormalities. The prevalence of this pathological event is increasing worldwide, and is intimately associated with obesity and type 2 diabetes mellitus, among other comorbidities. To date, only therapeutic strategies based on lifestyle changes have exhibited a beneficial impact on patients with NAFLD, but unfortunately this approach is often difficult to implement, and shows poor long-term adherence. For this reason, great efforts are being made to elucidate and integrate the underlying pathological molecular mechanism, and to identify novel and promising druggable targets for therapy. In this regard, a large number of clinical trials testing different potential compounds have been performed, albeit with no conclusive results yet. Importantly, many other clinical trials are currently underway with results expected in the near future. Here, we summarize the key aspects of NAFLD pathogenesis and therapeutic targets in this frequent disorder, highlighting the most recent advances in the field and future research directions.

Interactions between Tryptophan Metabolism, the Gut Microbiome and the Immune System as Potential Drivers of Non-Alcoholic Fatty Liver Disease (NAFLD) and Metabolic Diseases

“…Several inflammatory mechanisms in NAFLD are affected by metabolites of the microbe-derived indole pathway [75][76][77][78]. A potential driver of inflammation in NAFLD is the NF-kB pathway induced by the residential liver macrophages (Kupffer cells) [18,19]. In rodents, oral administration of indole after intraperitoneal injection of LPS reduced levels of cytokines Il-1β, Il-6 and Il-15, as well as levels of NF-kB [79].…”

“…LPS binds to toll like receptor 4 (TLR4) activating the innate immune system in the liver, especially Kupffer cells and infiltrating monocytes/macrophages [16,17]. Combined with activating the MyD88/NF-kB cascade, the binding of LPS to TLR4 induces the release of proinflammatory cytokines such as interleukin 6 (IL-6), IL-17, tumor necrosis factor α (TNF-α) and interferon γ (INF-γ), eventually leading to the release of fibrogenic factors [8,18,19].…”

Management of NAFLD in primary care settings

“…Furthermore, molecular mediators from various organs, particularly the adipose tissue and the gut, participate in triggering inflammation pathways, which may later progress to liver fibrosis and, eventually, carcinogenesis. 2,12 One of the studied mechanisms is the overactivation of the endocannabinoid system, which is related to various metabolic disorders and associated comorbidities. 13 Sarcopenia is another risk factor for NAFLD, which is in turn associated with the progression of sarcopenia.…”

“…Despite this, impairment in insulin signalling at the level of the adipose tissue and the liver seems to be a very early event (Figure 2). Furthermore, molecular mediators from various organs, particularly the adipose tissue and the gut, participate in triggering inflammation pathways, which may later progress to liver fibrosis and, eventually, carcinogenesis 2,12 . One of the studied mechanisms is the overactivation of the endocannabinoid system, which is related to various metabolic disorders and associated comorbidities 13 .…”

The correlation between triiodothyronine and the severity of liver fibrosis

“…Non-alcoholic fatty liver disease (NAFLD) is a clinicopathological syndrome characterized by hepatic steatosis [ 1 ]. It is a liver disease caused by other causes excluding alcohol, viral hepatitis, autoimmune liver disease and drugs, and has rapidly become a global public health problem [ 2 ]. NAFLD is a hepatic manifestation of the metabolic syndrome (MetS) and is also associated with many metabolic diseases including type 2 diabetes mellitus (T2DM), obesity, hyperlipidemia and arterial hypertension [ 3 ].…”