Multidimensional Biomarker Analysis Including Mitochondrial Stress Indicators for Nonalcoholic Fatty Liver Disease

Abstract

Nonalcoholic fatty liver disease (NAFLD) is accompanied by a complex and multifactorial pathogenesis with sequential progressions from inflammation to fibrosis and then to cancer. This heterogeneity interferes with the development of precise diagnostic and prognostic strategies for NAFLD. The current approach for the diagnosis of simple steatosis, steatohepatitis, and cirrhosis mainly consists of ultrasonography, magnetic resonance imaging, elastography, and various serological analyses. However, individual dry and wet biomarkers have limitations demanding an integrative approach for the assessment of disease progression. Here, we review diagnostic strategies for simple steatosis, steatohepatitis and hepatic fibrosis, followed by potential biomarkers associated with fat accumulation and mitochondrial stress. For mitochondrial stress indicators, we focused on fibroblast growth factor 21 (FGF21), growth differentiation factor 15 (GDF15), angiopoietin-related growth factor and mitochondrial-derived peptides. Each biomarker may not strongly indicate the severity of steatosis or steatohepatitis. Instead, multidimensional analysis of different groups of biomarkers based on pathogenic mechanisms may provide decisive diagnostic/prognostic information to develop a therapeutic plan for patients with NAFLD. For this purpose, mitochondrial stress indicators, such as FGF21 or GDF15, could be an important component in the multiplexed and contextual interpretation of NAFLD. Further validation of the integrative evaluation of mitochondrial stress indicators combined with other biomarkers is needed in the diagnosis/prognosis of NAFLD.

Keywords: Biomarkers; Fibroblast growth factor 21; Growth differentiation factor 15; Mitochondrial stress; Non-alcoholic fatty liver disease.

Fig. 1

Physiological regulation and functions of mitochondrial stress biomarkers. Physiological and pathophysiological conditions upregulating fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15) are listed above. FGF21 and/or GDF15 act on the liver, muscle, adipose tissue, brain, pancreatic islets, and other organs to relieve metabolic stress.

Fig. 2

Biomarkers for nonalcoholic fatty liver disease. Coordinated patterns of alterations in different types of serum markers during the progression of nonalcoholic fatty liver disease. RBP4, retinol binding protein 4; FGF21, fibroblast growth factor 21; GDF15, growth differentiation factor 15; TNF-α, tumor necrosis factor α; IL-6, interleukin 6; CCL2, C-C motif chemokine ligand 2; CXCLs, C-x-C motif chemokine ligands; TGF-β, transforming growth factor β; PAI-1, plasminogen activator inhibitor-1.