Hypothesis Targeting NTCP and BSEP as a Novel Therapeutic Intervention for the Management of Intra-hepatic Cholestatic Liver Injury

Abstract

The instance of metabolic dysfunction-associated steatotic liver disease (MASLD) is escalating at a concerning rate, with future estimations indicating a projected prevalence of 33.5% by 2030 worldwide, particularly among the adult population. The major causative factors of MASLD include excessive body weight, insulin resistance-associated diabetes and metabolic syndrome. Cholestasis, a key complication of MASLD, arises from metabolic distress, inflammation mediated-biliary transporter dysfunction, gut microbiota imbalance and excessive bile acid retention, resulting in the enhancement of hepatic injury and accelerating hepatic disease progression. Despite the availability of several therapeutic medications for cholestasis, these medications mainly address clinical manifestations rather than the underlying pathophysiological mechanisms of the diseased conditions. Therefore, there is a crucial need to explore more therapeutic treatment options that primarily focus on target-based intervention for cholestasis management. For the exploration of such therapeutic approaches, experimental models that reproduce specific mechanistic components of cholestatic liver injury are valuable for hypothesis generation and therapeutic target identification. Lipopolysaccharide (LPS)-induced cholestasis is a well-established experimental model in rodents, typically employing LPS derived from Escherichia coli (e.g., O111:B4) administered via intraperitoneal injection at doses ranging from 2.5 to 10 mg/kg either as a single dose (acute model, evaluated within 6–24 h) or repeated dosing over 2–5 days. Although LPS-induced cholestasis does not fully recapitulate the chronic metabolic pathology of MASLD, it provides a useful reductionist model for studying inflammation-driven hepatobiliary transporter dysfunction relevant to cholestatic liver injury. LPS precipitate the stimulation of toll-like receptor 4-induced nuclear factor-kappa B signalling, which further leads to the unleashing of inflammatory cytokines like tumour necrotic factor-α, interleukin (IL)-1, IL-8 and the downregulation of sodium taurocholate co-transporting polypeptide (NTCP), bile salt export pump (BSEP) and Farnesoid X receptor gene expression. This disrupted modulation in biliary transporters and nuclear receptors facilitates cholestasis, contributing to intra-hepatic bile acid accumulation and liver injury. In the present review, we propose a dual-target therapeutic approach aimed at restoring bile acid balance through simultaneous inhibition of NTCP-mediated hepatic uptake and enhancement of BSEP-mediated canalicular efflux through appropriate regulatory mechanisms. This flux-oriented approach provides a mechanistically distinct strategy for the management of cholestatic liver injury that warrants further experimental validation.