At the Forefront of NASH Research
STAM(TM) contract services available in Stelic
Posted on 4th Nov, 2011
Featured here is a therapeutic potential of angiotensin II receptor blockers (ARBs) for the treatment of nonalcoholic steatohepatitis (NASH).
Various attempts have been made to treat NASH, with focus on different aspects of the disease pathology (e.g. steatosis, lobular inflammation, pericellular fibrosis). In the exploration of such potential approaches, the renin-angiotensin system (RAS) is emerging as a promising target for intervention in NASH-related fibrosis [1].
The RAS consists of two processing enzymes renin and ACE (angiotensin-I converting enzyme), and of their substrate peptides angiotensinogen and angiotensins (see diagram below). Its active end product, angiotensin II (ATII), is a hormonal peptide, which circulates in the blood stream as well as acts in an autocrine/paracrine manner to elicit downstream signaling events in target cells [2].
The primary and best-known role of RAS is to control blood pressure by modulating blood vessel constriction and renal salt homeostasis. Recently, however, another role of RAS has been highlighted — the role of controlling profibrogenic events in activated hepatic stellate cells (HSCs), in which ATII receptors are highly expressed. RAS inhibition studies have suggested the involvement of NADPH oxidase, the NF-κB pathway, TGF-βsignaling and inflammatory cytokines in this fibrogenic HSC activation [3, 4].
Angiotensin II receptor blockers (ARBs) exert their effects by antagonizing ATII receptors and suppressing the downstream pathways of RAS. The drugs lower blood pressure and have been widely prescribed as antihypertensive agents. Consistent with the additional role of RAS described above, ARBs have also proved effective in NASH patients with hypertension, showing an amelioration of liver fibrosis in a clinical study [5]. Furthermore, a unique and distinctive therapeutic potential of each ARB has been reported in both clinical and non-clinical studies, including insulin sensitization and lipid-metabolism modification. The differences are supposed to be derived from their binding selectivity and pharmacokinetic profiles [1, 6]. Further studies on the mechanism of action and evaluation of dosing strategies for each ARB are worthwhile for their clinical application to NASH.
Stelic’s NASH-HCC model (STAM model) has been used for such tailored evaluations of anti-NASH candidates for its reproducibility and fidelity to human NASH. In fact, treatment of STAM mice with Telmisartan lowered serum ALT levels, improved NAFLD Activity score (NAS) and reduced collagen deposition in the liver, which were similar to reported results from human clinical studies [5, 7] and provided important suggestions for the optimal dosing regimen. For further details, please request a summary sheet of our preclinical service: info_research@stelic.co.jp
Key words: nonalcoholic steatohepatitis (NASH), renin-angiotensin system (RAS), liver fibrosis, angiotensin II receptor blocker (ARB), Telmisartan
References
1. Georgescu, EF., et al. (2008). Angiotensin receptor blockers in the treatment of NASH/NAFLD: could they be a first-class option? Adv. Ther., 25, 1141-74.
2. Lavoie, JL., et al., (2003). Minireview: overview of the renin-angiotensin system—an endocrine and paracrine system. Endocrinology, 144, 2179-83.
3. Munshi, MK., et al., (2011). The role of the renin—angiotensin system in liver fibrosis. Exp. Biol. Med., 236, 557-566.
4. Yokohama, S., et al., (2006). Inhibitory effect of angiotensin II receptor antagonist on hepatic stellate cell activation in non-alcoholic steatohepatitis. World J. Gastroenterol., 14, 322-6.
5. Georgescu, EF., et al., (2009). Angiotensin-receptor blockers as therapy for mild-to-moderate hypertension-associated non-alcoholic steatohepatitis. World J. Gastroenterol., 15, 942-54.
6. de Kloet, AD., et al., (2010). The renin angiotensin system and the metabolic syndrome. Physiol. Behav., 100, 525-34.
7. Enjoji, M., et al., (2008). Therapeutic effect of ARBs on insulin resistance and liver injury in patients with NAFLD and chronic hepatitis C: A pilot study. Int. J. Mol. Med., 22, 521-27.
