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

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.

Neuregulin-4 attenuates diabetic cardiomyopathy by regulating autophagy via the AMPK/mTOR signalling pathway

“…Nrg4 is a member of the epidermal growth factor family of extracellular ligands and has been found to be highly enriched in brown adipose tissue [ 37 ]. The adipokine Nrg4 plays an important role in regulating systemic energy metabolism and is involved in the pathogenesis of obesity-associated disorders, including DM and nonalcoholic fatty liver disease [ 38 ]. Previous investigations focused on the hypothesis that Nrg4 might play roles in the development of DM and circulating Nrg4 levels might be associated with an imbalance in glucose metabolism [ 39 , 40 ].…”

Increase of blood neuregulin 4 is associated with type 2 diabetes mellitus and hypertension in obese patients

“…Так, значительное снижение уровня NRG4 в крови обнаружено у детей и взрослых с ожирением, у пациентов с впервые диагностированным СД 2 типа [2,12,13]. Напротив, другие авторы не выявили изменений NRG4 в крови у больных НАЖБП [5]. В связи с вышесказанным, целью исследования явилась оценка содержания NRG4 в крови больных ожирением с СД 2-го типа и без него, с последующей оценкой взаимосвязей NRG4 с показателями углеводного и липидного обменов и наличием сопутствующих заболеваний.…”

Neuregulin 4 as a novel adipokine in energy metabolism

“…For each standard deviation increase in Nrg4 serum levels, a 41% reduction in the odds of NAFLD was identified after adjusting for confounding factors ( Tutunchi et al, 2021 ). However, another study illustrated that serum Nrg4 levels were not associated with NAFLD, hepatic fat fraction, and NAFLD-associated fibrosis in patients where chemical shift magnetic resonance imaging and transient elastography were used to diagnose NAFLD and associated fibrosis, respectively ( De Munck TJIBoesch et al, 2021 ). The different findings of these studies may be due to the heterogeneity of the study populations and methods, thus this is further evidence that the role of Nrg4 in the clinical setting may be influenced by multiple factors ( De Munck TJIBoesch et al, 2021 ).…”

“…However, another study illustrated that serum Nrg4 levels were not associated with NAFLD, hepatic fat fraction, and NAFLD-associated fibrosis in patients where chemical shift magnetic resonance imaging and transient elastography were used to diagnose NAFLD and associated fibrosis, respectively ( De Munck TJIBoesch et al, 2021 ). The different findings of these studies may be due to the heterogeneity of the study populations and methods, thus this is further evidence that the role of Nrg4 in the clinical setting may be influenced by multiple factors ( De Munck TJIBoesch et al, 2021 ). The limitations of these studies are the lack of representative data and the nature of observational studies to determine a causal relationship between Nrg4 and NAFLD, and larger well-designed studies are needed to validate this relationship in the future.…”