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. 2021 May 14;16(5):e0251822.
doi: 10.1371/journal.pone.0251822. eCollection 2021.

Is there a role for neuregulin 4 in human nonalcoholic fatty liver disease?

Toon J I De Munck  1   2 , Markus Boesch  3 , Pauline Verhaegh  1   2 , Ad A M Masclee  1   2 , Daisy Jonkers  1   2 , Jos F van Pelt  4 , Johannie du Plessis  3 , Hannelie Korf  3 , Frederik Nevens  3   5 , Ger H Koek  1   2 , Schalk Van der Merwe  3   5 , Jef Verbeek  3   5
Affiliations

Is there a role for neuregulin 4 in human nonalcoholic fatty liver disease?

Toon J I De Munck et al. PLoS One. .

Abstract

Background: Neuregulin 4 (Nrg4), a novel adipokine enriched in brown adipose tissue has been observed to negatively regulate de novo hepatic lipogenesis and limit nonalcoholic fatty liver disease (NAFLD) progression to nonalcoholic steatohepatitis (NASH) in rodents. However, the role of Nrg4 in human NAFLD remains unclear to date. We analysed Nrg4 plasma levels and its association with liver disease severity together with the transcriptional profile of the Nrg4 pathway in liver and visceral adipose tissue (VAT) of NAFLD patients.

Methods: Plasma Nrg4 levels were measured in 65 NAFLD patients and 43 healthy controls (HC). Hepatic steatosis and fibrosis were diagnosed and quantified with chemical shift MRI and transient elastography respectively. Furthermore, blood lipid levels, HOMA-IR and systemic pro-inflammatory cytokines (TNF-α, IL-6 and IFN-γ) were analysed. Microarray analyses to assess differences in the Nrg4 and its receptor family ErbB pathway in liver and VAT from an independent patient group with biopsy proven NAFL (simple steatosis) (n = 4), NASH (n = 5) and normal liver (n = 6) were performed.

Results: Plasma Nrg4 levels were not significantly different between NAFLD patients and HC (p = 0.622). Furthermore, plasma Nrg4 levels did not correlate with the hepatic fat fraction (r = -0.028, p = 0.829) and were not significantly different between NAFLD patients with or without hepatic fibrosis (p = 0.087). Finally, the expression profile of 82 genes related to the Nrg4-ErbB pathway in liver and VAT was not significantly different between NAFL, NASH or obese controls.

Conclusion: Our study does not support a role for Nrg4 in the pathophysiology of human NAFLD.

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Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. Plasma Nrg4 levels in NAFLD patients versus healthy controls.
Values are presented in scatter plots with median line (Q1, Q3). Plasma Nrg4 levels were compared between groups with the Mann-Whitney U-tests (A) and Kruskall Wallis test (B). Plasma Nrg4 levels in (A) HC versus NAFLD patients, (B) NAFLD patients with and without DM2 and HC. DM2, type 2 diabetes mellitus.
Fig 2
Fig 2. Association between plasma Nrg4 levels and NAFLD severity.
Values are presented in scatter plots with median line and (Q1, Q3). Spearman correlation was used for correlation analysis and Mann-Whitney U-tests for comparison between two groups. (A) Spearman correlation between hepatic fat fraction and plasma Nrg4 levels in NAFLD patients. (B) Plasma Nrg4 levels in NAFLD patients without clinically significant hepatic fibrosis (F0-1), versus NAFLD patients with clinically significant hepatic fibrosis (F2-3).
Fig 3
Fig 3. Heatmap of 82 NrG4-ErbB signalling pathway related genes.
Visualised as average Robust Multi-array Average (RMA) expressions in the liver and visceral adipose tissue of obese, NAFLD and NASH patients.
See this image and copyright information in PMC

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