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Repurposing drugs to target nonalcoholic steatohepatitis.

ABSTRACT: Nonalcoholic fatty liver disease (NAFLD) is a complex disorder that has evolved in recent years as the leading global cause of chronic liver damage. The main obstacle to better disease management pertains to the lack of approved pharmacological interventions for the treatment of nonalcoholic steatohepatitis (NASH) and NASH-fibrosis-the severe histological forms. Over the past decade, tremendous advances have been made in NAFLD research, resulting in the discovery of disease mechanisms and novel therapeutic targets. Hence, a large number of pharmacological agents are currently being tested for safety and efficacy. These drugs are in the initial pharmacological phases (phase 1 and 2), which involve testing tolerability, therapeutic action, and pharmacological issues. It is thus reasonable to assume that the next generation of NASH drugs will not be available for clinical use for foreseeable future. The expected delay can be mitigated by drug repurposing or repositioning, which essentially relies on identifying and developing new uses for existing drugs. Here, we propose a drug candidate selection method based on the integration of molecular pathways of disease pathogenesis into network analysis tools that use OMICs data as well as multiples sources, including text mining from the medical literature.

SUBMITTER: Sookoian S

PROVIDER: S-EPMC6478618 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Repurposing drugs to target nonalcoholic steatohepatitis.

Sookoian Silvia S Pirola Carlos J CJ

World journal of gastroenterology 20190401 15

Nonalcoholic fatty liver disease (NAFLD) is a complex disorder that has evolved in recent years as the leading global cause of chronic liver damage. The main obstacle to better disease management pertains to the lack of approved pharmacological interventions for the treatment of nonalcoholic steatohepatitis (NASH) and NASH-fibrosis-the severe histological forms. Over the past decade, tremendous advances have been made in NAFLD research, resulting in the discovery of disease mechanisms and novel ...[more]

PMID: 31057294

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Project description:The Nod-like receptor protein 3 (NLRP3) inflammasome activation not only serves as an intracellular machinery triggering inflammation but also produces uncanonical effects beyond inflammation such as changing cell metabolism and increasing cell membrane permeability. The present study was designed to test whether this NLRP3 inflammasome activation contributes to the "two-hit" injury during nonalcoholic steatohepatitis (NASH) and whether it can be a therapeutic target for the action of Fufang Zhenzhu Tiaozhi (FTZ), a widely used herbal remedy for hyperlipidemia and metabolic syndrome in China. We first demonstrated that NLRP3 inflammasome formation and activation as well as lipid deposition occurred in the liver of mice on the high-fat diet (HFD), as shown by increased NLRP3 aggregation, enhanced production of IL-1? and high mobility group box 1 (HMGB1), and remarkable lipid deposition in liver cells. FTZ extracts not only significantly reduced the NLRP3 inflammasome formation and activation but also attenuated the liver steatosis and fibrogenic phenotype changed. In in vitro studies, palmitic acid (PA) was found to increase colocalization of NLRP3 components and enhanced caspase-1 activity in hepatic stellate cells (HSCs), indicating enhanced formation and activation of NLRP3 inflammasomes by PA. PA also increased lipid deposition. Nlrp3 siRNA can reverse this effect by silencing the NLRP3 inflammasome and both with FTZ. In FTZ-treated cells, not only inflammasome formation and activation was substantially attenuated but also lipid deposition in HSCs was blocked. This inhibition of FTZ on lipid deposition was similar to the effects of glycyrrhizin, an HMGB1 inhibitor. Mechanistically, stimulated membrane raft redox signaling platform formation and increased O2•- production by PA to activate NLRP3 inflammasomes in HSCs was blocked by FTZ treatment. It is concluded that FTZ extracts inhibit NASH by its action on both inflammatory response and liver lipid metabolism associated with NLRP3 inflammasome formation and activation.

Project description:The heteromeric steroid transporter organic solute transporter ?/? (OST?/?, SLC51A/B) was discovered over a decade ago, but its physiological significance in the liver remains uncertain. A major challenge has been the lack of suitable models expressing OST?/?. Based on observations first reported here that hepatic OST?/? is upregulated in nonalcoholic steatohepatitis, the aim of this research was to develop an in vitro model to evaluate OST?/? function and interaction with drugs and bile acids. OST?/? expression in human liver tissue was analyzed by quantitative RT-PCR, Western blotting, and immunofluorescence. Radiolabeled compounds were used to determine OST?/?-mediated transport in the established in vitro model. The effect of bile acids and drugs, including those associated with cholestatic drug-induced liver injury, on OST?/?-mediated transport was evaluated. Expression of OST?/? was elevated in the liver of patients with nonalcoholic steatohepatitis and primary biliary cholangitis, whereas hepatocyte expression of OST?/? was low in control liver tissue. Studies in the novel cell-based system showed rapid and linear OST?/?-mediated transport for all tested compounds: dehydroepiandrosterone sulfate, digoxin, estrone sulfate, and taurocholate. The interaction study with 26 compounds revealed novel OST?/? inhibitors: a biomarker for cholestasis, glycochenodeoxycholic acid; the major metabolite of troglitazone, troglitazone sulfate; and a macrocyclic antibiotic, fidaxomicin. Additionally, some drugs (e.g., digoxin) consistently stimulated taurocholate uptake in OST?/?-overexpressing cells. Our findings demonstrate that OST?/? is an important transporter in liver disease and imply a role for this transporter in bile acid-bile acid and drug-bile acid interactions, as well as cholestatic drug-induced liver injury. NEW & NOTEWORTHY The organic solute transporter OST?/? is highly expressed in hepatocytes of liver tissue obtained from patients with nonalcoholic steatohepatitis and primary biliary cholangitis. OST?/? substrates exhibit rapid, linear, and concentration-driven transport in an OST?/?-overexpressing cell line. Drugs associated with hepatotoxicity modulate OST?/?-mediated taurocholate transport. These data suggest that hepatic OST?/? plays an essential role in patients with cholestasis and may have important clinical implications for bile acid and drug disposition.

Dataset Information

Repurposing drugs to target nonalcoholic steatohepatitis.

Publications

Repurposing drugs to target nonalcoholic steatohepatitis.

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