Cyclo(His-Pro): A further step in the management of steatohepatitis

Alessia De Masi; Xiaoxu Li; Dohyun Lee; Jongsu Jeon; Qi Wang; Seoyeong Baek; Onyu Park; Adrienne Mottis; Keno Strotjohann; Alexis Rapin; Hoe-Yune Jung; Johan Auwerx

doi:10.1016/j.jhepr.2023.100815

Cyclo(His-Pro): A further step in the management of steatohepatitis

JHEP Rep. 2023 Jun 10;5(9):100815. doi: 10.1016/j.jhepr.2023.100815. eCollection 2023 Sep.

Authors

Affiliations

¹ Laboratory of Integrative Systems Physiology, Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
² R&D Center, NovMetaPharma Co., Ltd., Pohang, South Korea.
³ School of Interdisciplinary Bioscience and Bioengineering, Pohang University of Science and Technology (POSTECH), Pohang, South Korea.

Abstract

Background & aims: Non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) have become the world's most common liver diseases, placing a growing strain on healthcare systems worldwide. Nonetheless, no effective pharmacological treatment has been approved. The naturally occurring compound cyclo histidine-proline (His-Pro) (CHP) is an interesting candidate for NAFLD management, given its safety profile and anti-inflammatory effects.

Methods: Two different mouse models of liver disease were used to evaluate protective effects of CHP on disease progression towards fibrosis: a model of dietary NAFLD/NASH, achieved by thermoneutral housing (TN) in combination with feeding a western diet (WD), and liver fibrosis caused by repeated injections with carbon tetrachloride (CCl₄).

Results: Treatment with CHP limited overall lipid accumulation, lowered systemic inflammation, and prevented hyperglycaemia. Histopathology and liver transcriptomics highlighted reduced steatosis and demonstrated remarkable protection from the development of inflammation and fibrosis, features which herald the progression of NAFLD. We identified the extracellular signal-regulated kinase (ERK) pathway as an early mediator of the cellular response to CHP.

Conclusions: CHP was active in both the preventive and therapeutic setting, reducing liver steatosis, fibrosis, and inflammation and improving several markers of liver disease.

Impact and implications: Considering the incidence and the lack of approved treatments, it is urgent to identify new strategies that prevent and manage NAFLD. CHP was effective in attenuating NAFLD progression in two animal models of the disease. Overall, our work points to CHP as a novel and effective strategy for the management of NAFLD, fuelling optimism for potential clinical studies.

Keywords: Cyclo histidine-proline (Cyclo(His-Pro)); Drug development; Inflammation; Liver; Liver fibrosis; Non-alcoholic fatty liver disease; Non-alcoholic steatohepatitis; Prevention; Therapeutics; Transcriptomics.