Drugs for Non-alcoholic Steatohepatitis (NASH): Quest for the Holy Grail

Abstract

Nonalcoholic fatty liver disease (NAFLD) is a global epidemic that is likely to become the most common cause of chronic liver disease in the next decade, worldwide. Though numerous drugs have been evaluated in clinical trials, most of them have returned inconclusive results and shown poorly-tolerated adverse effects. None of the drugs have been approved by the Food and Drug Administration for treating biopsy-proven non-alcoholic steatohepatitis (NASH). Vitamin E and pioglitazone have been extensively used in treatment of biopsy-proven nondiabetic NASH patients. Although some amelioration of inflammation has been seen, these drugs did not improve the fibrosis component of NASH. Therefore, dietary modification and weight reduction have remained the cornerstone of treatment of NASH; moreover, they have shown to improve histological activity as well as fibrosis. The search for an ideal drug or 'Holy Grail' within this landscape of possible agents continues, as weight reduction is achieved only in less than 10% of patients. In this current review, we summarize the drugs for NASH which are under investigation, and we provide a critical analysis of their up-to-date results and outcomes.

Keywords: Fatty liver; NAFLD; NASH; Obeticholic acid; Saroglitazar.

Fig. 1. Factors implicated in the pathogenesis of NASH and possible drug targets.

The factors which lead to NAFLD are depicted in the outer circle, while the changes that occur inside the liver are shown within the red circle. The drug targets are shown in blue lightening arrows. Abbreviations: FXR, farnesoid X receptor; PNPLA, patatin-like phospholipase domain-containing protein A; PPAR, peroxisome proliferator-activated receptors; TM6SF4, transmembrane 6 superfamily 2 human gene; Vit E, vitamin E.

Fig. 2. Proposed mechanism of action of OCA in NASH.

In the small intestine (orange cylinder) OCA binds to FXR receptors and through formation of the β-klotho-FGF4-FGF19 complex inhibits CYP7A1 and decreases bile acid synthesis. OCA increases the expression of the bile salt exporter protein BSEP and the multidrug resistance 3 protein MDR3, promoting efflux of bile from liver. OCA also decreases stellate cell (green star) activation, leading to decrease in fibrosis. OCA within the enterocytes leads to increased GLP-1 formation and improves insulin sensitivity. Abbreviations: ASBT, apical sodium-dependent bile acid transporter; BA, bile acid; CYP7A1, cytochrome P450 family 7 subfamily A member 1; FGF, fibroblast growth factor; GLP-1, glucagon-like peptide-1.

Fig. 3. Mechanism of action of saroglitazar in NASH.

The pathophysiology of NASH is depicted in the pathway with black arrows. Saroglitazar increases beta-oxidation (green arrows) and decreases lipolysis (red arrows), leading to decrease in free fatty acids. In addition, it reduces ER stress and stellate cell activation (red arrows). This leads to decreased hepatic steatosis and inflammation, reduction in hepatic fibrosis, and improvement in insulin resistance. Abbreviations: ER, endoplasmic reticulum; FFA, free fatty acid IL-6, interleukin-6; ROS, reactive oxygen species; TG, triglyceride; TNF, tumor necrosis factor; VLDL, very low-density lipoprotein.