NAFLD is characterized by lipid deposition in liver cells and is progressed to NASH
and HCC. Hepatocyte (HC)-derived Glycoprotein non-metastatic melanoma B (Gpnmb) was
recently reported as a regulator of fat metabolism in adipose tissue, however, its
role in the pathogenesis of NASH-related HCC are not clear. We aim to functionally
investigate Gpnmb during liver steatogenesis and HCC. A NASH-based HCC mouse model,
STAM was selected. In this model, NASH and HCC stages were analyzed. We also investigated
publically available patient cohorts i.e. GSE48452 (NASH) and GSE14520 (HCC) datasets.
An in vitro steatosis model was induced by oleic acid (OA) in primary mouse hepatocytes
(PMHC) and AML-12. GPNMB expression was manipulated by overexpression (OE) and knockdown
(KD) approaches. Steatosis induction and lipid metabolic targets was assessed upon
modulation of GPNMB by PCR. Cell growth and death of Huh7 cells was analysed by MTT
and caspase-3 assay, PCR, WB and time-lapse imaging. Comparative analysis of patient
cohorts and STAM mouse model identifies GPNMB as a consistently upregulated gene.
IHC staining shows that GPNMB protein localizes in HC in healthy and NASH, and in
HC-derived tumour cells in HCC tissues. In vitro, OA induces GPNMB in PMHC and AML-12
cells. Lipid accumulation increased upon KD of Gpnmb, and decreased by OE as measured
by triglyceride (TG) level in OA-treated pMHC and AML-12 cells. We analyzed GPNMB
dependent gene expression alterations of critical players in hepatic lipogenesis i.e.
SREBP-1c, PPAR-α, PPARγ, Fasn and Scd1, as well as targets involved in FA oxidation
as Cpt1 and Acox1. In line with TG accumulation, Gpnmb KD increases SREBP-1c, PPAR-α,
PPARγ, Fasn and Scd1 mRNA expression in OA-treated PMHC and AML12. However, Cpt1 and
Acox1 are also upregulated. In case of GPNMB OE, we obtained complementary results.
Preliminary data using Huh7 cells indicate that GPNMB OE suppresses cell proliferation
and induces apoptosis. Mechanistically, GPNMB OE facilitates cell death via inhibition
of AKT phosphorylation. GPNMB is a consistently upregulated target in NASH and HCC.
In contrast to previous reports, GPNMB is expressed in HC and HC-derived cancer cells,
instead of macrophages. In fatty liver, GPNMB is upregulated to tone down lipogenesis,
therefore, it seems that GPNMB has a protective role against liver fat toxicity. In
liver cancer cells, GPNMB acts as a tumor suppressor by providing cytostatic effects.
