Abstract
The prevalence of non-obese nonalcoholic fatty liver disease (NAFLD) is increasing worldwide with unclear etiology and pathogenesis. Here, we show GP73, a Golgi protein upregulated in livers from patients with a variety of liver diseases, exhibits Rab GTPase-activating protein (GAP) activity regulating ApoB export. Upon regular-diet feeding, liver-GP73-high mice display non-obese NAFLD phenotype, characterized by reduced body weight, intrahepatic lipid accumulation, and gradual insulin resistance development, none of which can be recapitulated in liver-GAP inactive GP73-high mice. Common and specific gene expression signatures associated with GP73-induced non-obese NAFLD and high-fat diet (HFD)-induced obese NAFLD are revealed. Notably, metformin inactivates the GAP activity of GP73 and alleviates GP73-induced non-obese NAFLD. GP73 is pathologically elevated in NAFLD individuals without obesity, and GP73 blockade improves whole-body metabolism in non-obese NAFLD mouse model. These findings reveal a pathophysiological role of GP73 in triggering non-obese NAFLD and may offer an opportunity for clinical intervention.
Highlights
The prevalence of non-obese nonalcoholic fatty liver disease (NAFLD) is increasing worldwide with unclear etiology and pathogenesis
Data are presented as mean ± SEM. *P < 0.05; **P < 0.01. g, h Glucose levels in blood samples of 6 h-fasted associated virus (AAV)-V- or AAV-GP73-injected mice at 4 (g) and 6 (h) months after injection (n = 6 per group)
Data are presented as mean ± SEM. *P < 0.05; **P < 0.01. i Glucose tolerance test (GTT) results for AAV-V- or AAV-GP73-injected mice at 4.5 months after injection (n = 6 per group)
Summary
The prevalence of non-obese nonalcoholic fatty liver disease (NAFLD) is increasing worldwide with unclear etiology and pathogenesis. GP73 is pathologically elevated in NAFLD individuals without obesity, and GP73 blockade improves whole-body metabolism in non-obese NAFLD mouse model. Individuals with non-obese NAFLD are metabolically unhealthy and have a higher risk of type 2 diabetes mellitus (T2DM), an accelerated development of advanced fibrosis and a greater incidence of severe liver disease than those with obese NAFLD. Risk factors other than obesity may play a key role in the pathophysiology of NAFLD in the non-obese population. Elucidating the specific mechanisms leading to the development and worse outcome of individuals with non-obese NAFLD will promote the ability of healthcare systems to develop appropriate guidance and interventions to treat this liver disease
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