Emerging Therapeutic Targets and Experimental Drugs for the Treatment of NAFLD

Abstract

The two main subsets of nonalcoholic fatty liver disease (NAFLD) include: (1) nonalcoholic fatty liver (NAFL), the more common and non-progressive subtype; and (2) nonalcoholic steatohepatitis (NASH), the less common subtype, which has the potential to progress to advanced liver damage. Current treatment strategies have focused on lifestyle management of modifiable risk factors, namely weight, and on the optimization of the management of individual components of metabolic syndrome. Various hypothetical pathogenic mechanisms have been proposed, leading to the development of novel drugs with the potential to effectively treat patients with NASH. Numerous clinical trials are ongoing, utilizing these experimental drugs and molecules targeting specific mechanistic pathway(s) to effectively treat NASH. Some of these mechanistic pathways targeted by experimental pharmacologic agents include chemokine receptor 2 and 5 antagonism, inhibition of galectin-3 protein, antagonism of toll-like receptor 4, variation of fibroblast growth factor 19, agonism of selective thyroid hormone receptor-beta, inhibition of apoptosis signal-regulating kinase 1, inhibition of acetyl-coenzyme A carboxylase, agonism of farnesoid X receptor, antibodies against lysl oxidase-like-2, and inhibition of inflammasomes. Emerging data are promising and further updates from ongoing clinical trials are eagerly awaited.

The Intricate Relationship between Type 2 Diabetes Mellitus (T2DM), Insulin Resistance (IR), and Nonalcoholic Fatty Liver Disease (NAFLD)

“…Efforts are currently in progress to find new promising treatment options to combat NAFLD [122]. In lack of a concrete pharmacotherapy, the current guidelines recommendation for NAFLD mainly emphasize revisions of lifestyle [108,132].…”

Diet, Gut Microbiota and Non-Alcoholic Fatty Liver Disease: Three Parts of the Same Axis

“…An incidence between 20% and 30% is estimated within of the adult population in Western countries. Meanwhile, in Eastern societies, this disease presents a lower prevalence, although some recent studies are pointing at the fact that its incidence is rising due to changes in Eastern nutritional habits, together with a decreasing of physical activity that is typical of a sedentary lifestyle ("Westernized society") [2]. Regarding nutrition, an improper and excessive intake of saturated fats and caloric oversupply, together with a low intake of vegetables, fruits, proteins, grains and ω3-fatty acids, are key causes to develop NAFLD [3].…”

“…NAFLD shows two main stages: The most common stage is nonalcoholic fatty liver (NAFL), a non-progressive and less-dangerous state of the liver condition, whereas nonalcoholic steatohepatitis (NASH) is less frequent, but its potential progression to advanced liver damage is worryingly difficult to revert, and could trigger worst diagnoses such as fibrosis progression, cirrhosis or even hepatocarcinoma (HCC) [2,7]. The principal causes of NASH are steatosis, hepatocyte ballooning and lobular inflammation, and it can only be diagnosed by liver biopsy, which is the only existing reliable diagnosis method nowadays [7].…”

An Integrated Approach Exploring the Synergistic Mechanism of Herbal Pairs in a Botanical Dietary Supplement: A Case Study of a Liver Protection Health Food

“…Accordingly, the underlying mechanism of the White Peony-Licorice pair on protecting against chemical-induced liver injury could be explained by regulating chemicals, drugs, and xenobiotic metabolism via CYP enzymes to reduce cellular dysfunction; preventing canalicular and cholestatic injury by regulating membrane transporters involved in ABC transporters and bile secretion pathway to promote bile acid formation and movement; decreasing immune response and inflammation by regulating NF-kappa B, TNF, VEGF, mTOR, MAPK, AMPK, Toll-like receptor, and NOD-like receptor signaling pathways; and reducing cell death via apoptosis and p53 signaling pathways. NAFLD is the accumulation of fat within the hepatocytes when import or synthesis of fat exceeds its export or degradation [45]. The NAFLD pathway (KEGG:04932) is complicated and composed of multiple pathways, including type II diabetes mellitus, fatty acid biosynthesis, protein processing in endoplasmic reticulum, apoptosis, oxidative phosphorylation, PI3K-ATP, insulin signaling, adipocytokine signaling, PPAR signaling, and TNF signaling pathways.…”