Thyroid hormones as a disease modifier and therapeutic target in nonalcoholic steatohepatitis

ABSTRACT

Introduction

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide and closely interconnected to the metabolic syndrome. Liver-specific and systemic signaling pathways orchestrating glucose and fatty acid metabolism contribute to intrahepatic accumulation of lipids and inflammatory processes eventually causing disease progression to nonalcoholic steatohepatitis (NASH), liver fibrosis, and cirrhosis. Since a high number of key regulatory genes regarding liver homeostasis are directly mediated via thyroid hormone (TH) signaling, targeting TH receptors (TRs) represent a promising therapeutic potential for the treatment of NAFLD.

Areas covered

In this review, we elucidate the effects of TH on metabolic regulations in the liver via local availability and actions. We discuss recent advances and the potential impact of thyromimetics in basic research and clinical trials including liver-targeted and TRβ-specific agents for the treatment of NAFLD.

Expert opinion

Unselective TR targeting can be accompanied by negative side effects due to high TRβ expression in other organs and TRα-mediated effects. Recent advances in drug development and the introduction of liver-targeted thyromimetics selectively activating TRβ such as Resmetirom (MGL-3196) and VK2809 bring new hope of translating the knowledge on local TH effects into effective hepatic lipid-clearing therapies against NASH.

KEYWORDS:

• NAFLD
• nonalcoholic steatohepatitis (NASH)
• thyroid hormones
• thyromimetics
• thyroid hormone receptor agonists
• THR

Article highlights

• Thyroid hormones are critical regulators of local energy metabolism and act by altering carbohydrate and fatty acid metabolism in the liver.

• (Sub)clinical hypothyroidism predisposes patients towards the development of fatty liver disease.

• Local concentrations and actions of thyroid hormones mediated via altered uptake, metabolism, and receptor signaling are differentially regulated in NAFLD and NASH.

• Liver-targeted TRβ-specific thyromimetics propose valuable therapy options omitting TH-related side effects.

• Recent data from phase 3 trials using Resmetirom (MGL-3196) indicate the effective reduction in hepatic and serum lipids, triglycerides, and liver enzymes together with a reduction in non-invasive markers of liver fibrosis while being safe and well tolerated.

Declaration of interest

F Tacke’s lab has received research funding from Allergan, Bristol-Myers Squibb, Gilead and Inventiva. The funders had no role in the design of the study, in collection, analysis, or interpretation of the data, in the writing of the manuscript, or the decision to publish the results.

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This work was supported by the German Research Foundation (DFG SFB/TRR 296 and CRC 1382, Project-ID 403224013). T Puengel is funded through the Berlin Institute of Health (BIH) Clinician Scientist Program.