Obeticholic acid: expanding the therapeutic landscape of NASH

Abstract

Currently treatment options for Non-Alcoholic Steatohepatitis (NASH), the aggressive form of nonalcoholic fatty liver disease (NAFLD) and one of the commonest causes of cirrhosis worldwide, are mainly limited to promotion of life style changes in diet and exercise habits as well as to control of comorbidities such as type 2 diabetes mellitus and dyslipidemia.1,2 With regard to pharmacotherapy, the armamentarium to treat NASH is rather limited and currently only vitamin E and pioglitazone are recommended in selected patients although their longterm benefit has not been demonstrated and some caution has been recommended due to potentially unwanted side-effects of these drugs.3 Indeed, several additional agents are in the therapeutic pipeline and are currently being tested in controlled trials as can be checked in open databases such as ClinicalTrials.gov (https://clinicaltrials.gov). The therapeutic targets being tackled are diverse and derive from recent basic and clinical research that had identified factors involved in NASH pathogenesis and progression. Among these factors are insulin resistance (IR), adipokine/cytokine imbalance, excessive oxidative stress, dysregulation of both lipid and carbohydrate metabolism and ongoing fibrogenesis. Most of the above mentioned factors are directly or indirectly regulated by the farnesoid X receptor (FXR), a nuclear hormone receptor regulated by bile acids (BAs), thus rendering the agonism of this receptor a potentially useful pharmacological target to treat NASH. This contention had previous support from pre-clinical studies4,5 and the recent publication of the FLINT study, a multicenter, randomized and placebo controlled trial examining the effects of obeticholic acid (OA), a synthetic FXR agonist, in patients with steatohepatitis opens windows of hope about counting with effective drugs for treating NASH. Before getting into details on the trial itself, a word about the molecular pathways on which FXR agonists could exert potentially beneficial effects in NASH is in order. In the last decade, BA have emerged as key metabolic modulators due to their ability to act as ligands of nuclear and membrane receptors. After the seminal reports demonstrating that FXR acts as an intracellular sensor for BA6,7 and that its deficiency determines important alterations in lipid and carbohydrate metabolism8,9 a wealth of information has accumulated regarding the critical role of FXR in a variety of cellular processes in different tissues mainly in the liver and intestine. As a transcription factor, when FXR is activated by a ligand (i.e. the natural bile acid chenodeoxycholic acid or the synthetic compound OA) heterodimerizes with a partner nuclear receptor, the retinoid X receptor α, and then translocates to the nucleus regulating the expression of multiple target genes. One of these genes is the short heterodimer partner, SHP that controls the expression of cholesterol 7α-hydroxylase (CYP7A1), the key enzyme in BA synthesis. Through this pathway, along with controlling BA import and export through the regulation of membrane transporters, FXR regulates intracellular BA levels, which is critical for preventing hepatocyte injury and death.10 Details of all additional target genes of FXR signaling is beyond the scope of this commentary and can be found elsewhere,11,12 but among those hepatic FXR targets that relevant to NASH pathophysiology the following deserve to be mentioned: