ReviewGene to screenFarnesoid X receptor targeting to treat nonalcoholic steatohepatitis
Highlights
► FXR is the bile acid nuclear receptor regulating lipid and glucose metabolism, and inflammatory responses. ► FXR-mediated activities have promoted a new understanding of bile acids as hormones with potential for multiple therapeutic applications. ► OCA is a potent and selective clinical-stage FXR agonist. ► Preclinical and clinical data support further clinical testing of OCA in NAFLD/NASH patients.
Introduction
Nonalcoholic fatty liver disease (NAFLD) is considered to be the hepatic manifestation of the metabolic syndrome, a cluster of interrelated clinical features, including insulin resistance with elevated fasting glycemia, dyslipidemia, hypertension and visceral obesity [1]. Nonalcoholic steatohepatitis (NASH), characterized by hepatocyte damage, inflammation and fibrosis, develops in a significant proportion of subjects with NAFLD through mechanisms still incompletely understood and can lead to cirrhosis and hepatocellular carcinoma [2]. NAFLD is currently the most prevalent chronic liver disease worldwide, affecting 20–40% of the general population in industrialized countries, and among all subjects with NAFLD at least 10–20% develop the more clinically worrisome features of NASH [3]. Remarkably, NASH as an indication for liver transplant has grown from 1% to 10% of all cases over the past decade, rapidly establishing the disease as the third most common indication for transplant behind hepatitis C and alcoholic liver disease [4]. NASH is thus becoming a major health issue in close association with the worldwide epidemic of obesity and diabetes.
Several factors have been implicated in the transition of NAFLD to NASH. While liver steatosis is the first of two possible ‘hits’ in the pathogenesis of NASH [5], insulin resistance, visceral adipose tissue expansion, oxidative stress, hypoadiponectinemia and inflammation, all represent amplifying mechanisms for the disease 6, 7. Insulin resistance is probably the main driver of NAFLD but also has an important role in the initiation and perpetuation of NASH, including fibrosis progression [8]. Other endocrine disorders are also potentially involved in NASH pathogenesis [9]. However, of the various factors involved, inflammation probably represents a key component of the ‘second hit’. This has been recently supported by the observation that deficiency in NLRP6 and NLRP3 inflammasomes and IL-18 changes the gut microbiota configuration enhancing the influx of Toll-like receptor (TLR)4 and TLR9 agonists into the portal circulation, which increase hepatic TNF-α production driving NASH progression [10]. Thus, transmissible colitogenic microbiota present in inflammasome-deficient mice enhance NASH development, and alterations in intestinal microbiome associated with inflammasome deficiencies could account for hepatic inflammatory responses promoting the transition from NAFLD to NASH.
At present, the only effective treatment for NAFLD and NASH is weight loss, associated with lifestyle modifications [11] and no drug has been approved for these indications. Given the key role of insulin resistance in the pathogenesis of NASH, glitazones, peroxisome proliferator-activated receptor-γ (PPAR-γ) agonists used as insulin sensitizers for the treatment of type 2 diabetes (e.g. pioglitazone), have been extensively tested, demonstrating the ability to reduce aminotransferase levels and induce a strong antisteatotic response in NASH patients [12]. In a phase II double blind, placebo controlled 24-month study, treatment with pioglitazone led to clear metabolic and histologic improvements (reductions in steatosis, inflammation, and ballooning necrosis), but it did not significantly reduce fibrosis as compared to placebo plus dietary intervention [13]. Subsequent studies have confirmed improvements in inflammation and liver cell injury but none have convincingly demonstrated an effect on fibrosis regression [12]. A recent large study failed to confirm a beneficial histological effect on fibrosis by pioglitazone, although both pioglitazone and the RRR-α-tocopherol form of vitamin E (formerly known as d-α-tocopherol) significantly reduced liver inflammation and steatosis [14]. Moreover, concerns about cardiovascular safety and increased bladder cancers following treatment with glitazones have been raised [15]. In pediatric NAFLD patients neither vitamin E nor metformin was superior to placebo in attaining the primary endpoint of sustained reduction in alanine transaminase (ALT) levels [16]. Thus, correcting insulin resistance is necessary but not sufficient for effectively treating NASH in the majority of patients [12], suggesting the need for broader hepatoprotective effects also targeting fibrogenic pathways. Combining insulin-sensitizing with additional hepatoprotective antifibrotic and anti-inflammatory properties in a single drug represents indeed an attractive therapeutic approach in NASH.
A promising new approach along these lines is based on recent discoveries of the key role played by bile acids (BAs) in regulating liver and metabolic homeostasis, revealing that they are much more than simple detergents facilitating the absorption of nutrients from the gastrointestinal tract. BAs modulate several nuclear hormone receptors, in particular the farnesoid X receptor (FXR) 17, 18, 19. BAs are also agonists for the G protein-coupled receptor TGR5 (Takeda G protein-coupled receptor 5) 20, 21. Signaling through FXR and TGR5 modulates several metabolic pathways, regulating not only BA synthesis and enterohepatic recirculation, but also triglyceride, cholesterol, glucose and energy homeostasis [22]. In addition, BAs display well documented anti-inflammatory and antifibrotic properties [22]. Therefore, these agents represent interesting candidates for the treatment of several chronic liver and metabolic diseases, including NASH.
Section snippets
The potential of FXR agonists for the treatment of NASH
FXR, a member of the nuclear receptor superfamily, is mainly expressed in liver, intestine, kidney and, to a lower extent, in adipose tissue [23]. It regulates, directly or through the orphan nuclear receptor small heterodimer partner (SHP), a wide variety of target genes critically involved in the control of BA, lipid, and glucose homeostasis, and in the regulation of immune responses (Table 1). In addition, FXR transcriptionally regulates genes controlling coagulation, vascular remodeling,
Preclinical evidence for beneficial effects of obeticholic acid in NASH
Obeticholic acid (OCA, also known as INT-747), a 6α-ethyl derivative of chenodeoxycholic acid (CDCA), is a first-in-class selective FXR agonist, originally described for its anticholestatic and potentially broader hepatoprotective properties [49]. The generation of OCA through the addition of the ethyl group to CDCA – a primary human BA and the natural FXR agonist in human – confers approximately 100-fold greater FXR agonistic activity in the nanomolar range [50]. The structural basis for this
Clinical experience with OCA
OCA has been evaluated in three phase II clinical studies, one in patients with type 2 diabetes and NAFLD, and two in patients with PBC. In addition, a large US multi-center, 18-month phase IIb study of OCA in NASH patients is currently ongoing.
Concluding remarks
As reviewed, FXR agonists could have a beneficial role in the treatment of NAFLD and/or NASH by decreasing hepatic lipogenesis, steatosis and insulin resistance, while also inhibiting inflammatory and fibrogenic responses which can promote liver cirrhosis and hepatocellular carcinoma in NASH patients. The preclinical evidence and the clinical experience with the first-in-class FXR agonist OCA, along with its proven efficacy in PBC patients and potential therapeutic applicability in several
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