Wnt/beta-catenin signaling inhibitors and nonalcoholic fatty liver disease: Potential therapeutic implications

Stergios A Polyzos ,, Jnnis Kountours , Athnsios D Anstsilkis , Evngelos Terpos

a First Laboratory of Pharmacology, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Macedonia, Greece

b Second Medical Clinic, Aristotle University of Thessaloniki, Ippokration Hospital, Thessaloniki, Macedonia, Greece

c Department of Endocrinology, 424 General Military Hospital, Thessaloniki, Macedonia, Greece

d Department of Clinical Therapeutics, School of Medicine, National and Kapodestrian University of Athens, Athens, Greece

TotheEditor:

We read with considerable interest the paper of Shree Harini and Ezhilarasan, summarizing the possible pathophysiological connections between the modulators of canonical Wnt/β-catenin pathway and nonalcoholic fatty liver disease (NAFLD) [1].The authors supported with evidence that Wnt/β-catenin signaling contributes to hepatic homeostasis by regulating hepatic development,regeneration and metabolism.They also supported that dysregulation of modulators of Wnt/β-catenin signaling is not only implicated in the development of NAFLD, but also in its progression to nonalcoholic steatohepatitis (NASH), hepatic fibrosis and hepatocellular carcinoma (HCC).

Sclerostin and Dickkopf-1 (DKK-1) are inhibitors of the canonical Wnt/β-catenin signaling, thereby inhibiting osteoblast differentiation and bone formation [2].Ten years ago, it was shown for the first time that circulating sclerostin was lower in women with postmenopausal osteoporosis than those without [3], a finding consistent in subsequent studies.Although circulating sclerostin may be downregulated in patients with postmenopausal osteoporosis [3], romosozumab, a humanized monoclonal antibody against sclerostin, has been approved for the treatment of postmenopausal osteoporosis, possibly being the most potent antiosteoporotic treatment to date [4].

Except for bone metabolism, Wnt/β-catenin pathway seems to be implicated in the pathophysiology of metabolic syndrome, including insulin resistance, dyslipidemia, obesity and type 2 diabetes [5], which are all closely associated with NAFLD [6].It was previously shown, in a study of biopsy-proven NAFLD patients, a progressive decline in circulating sclerostin levels from controls to patients with simple steatosis and then to those with NASH [7].Within NAFLD patients, high circulating DKK-1 levels were also shown to be associated with NASH, independently from potential cofounders [7].A more recent study also reported lower circulating sclerostin in NAFLD patients than in controls [8].

These observations may be important in the light of the approval of romosozumab for postmenopausal osteoporosis [4], as well as investigative antibody targeting DKK-1 or even bispecific antibody targeting both sclerostin and DKK-1 [9].Since there is to date no medication specifically approved for NAFLD, a disease estimated to affect 25% of the global adult population [6], the potential pathophysiological implication of sclerostin and DKK-1 in the pathogenesis of NAFLD may meet certain therapeutic potential in the near future.In this regard, the effect of romosozumab on NAFLD in women with postmenopausal osteoporosis and concomitant NAFLD may deserve investigation.

Acknowledgments

None.

CRediT authorship contribution statement

Stergios A Polyzos:Conceptualization, Data curation, Investigation, Methodology, Project administration, Supervision, Validation,Writing - original draft, Writing - review & editing.Jannis Kountouras:Validation, Writing - review & editing.Athanasios D Anastasilakis:Validation, Writing - review & editing.Evangelos Terpos: Validation, Writing - review & editing.

Funding

None.

Ethical approval

Not needed.

Competing interest

Athanasios D Anastasilakis has received lecture fees from UCB.Stergios A Polyzos, Jannis Kountouras, and Evangelos Terpos have no conflict of interest to declare.