Granulocyte colony stimulating factor treatment in non-alcoholic fatty liver disease: beyond marrow cell mobilization

Abstract

Protective effects of granulocyte colony stimulating factor (G-CSF) in acute liver injury via marrow cell mobilization have been reported in several studies. But exact mode of action and optimal protocol of G-CSF has been still doubt in chronic disease. Here we investigated mode of action and optimization of G-CSF as a treatment for non-alcoholic fatty liver disease (NAFLD). Various doses of conventional G-CSF (30 μg/kg once weekly, once daily for 5 days, twice weekly) and long acting G-CSF (30 μg/kg once a month) were evaluated in two kinds of NAFLD animal models to optimize the G-CSF protocol. G-CSF receptor expression highest increased in NAFLD model among various liver diseases compare to control (NAFLD: 14.7 times, alcohol hepatitis: 7.1 times, cirrhosis: 2.4 times, and ischemia reperfusion: 6.8 times). G-CSF treatment reduced intrahepatic fat accumulation, and inflammation in two kinds of NAFLD animal models. G-CSF increased PI3K/Akt expression in hepatocyte as well as decreased apoptotic drive (increased Bcl-2 expression and decreased Bax expression) in animal model. Five day consecutive G-CSF treatment and once a month long acting G-CSF increased marrow derived stem cell marker in peripheral blood. But twice a week conventional G-CSF treatment did not increased CD34+ cell in peripheral blood and liver neither. Not only high dose G-CSF (once daily for 5 days) but also hepatotropic dose G-CSF (twice a week) significantly reduced hepatocyte apoptosis via PI3K and Akt pathway activation without marrow cell mobilization in NAFLD animal model.

Maternal prebiotic supplementation reduces fatty liver development in offspring through altered microbial and metabolomic profiles in rats

“…Protective effects of G‐CSF on liver injury and damage have been noted in the literature both clinically and preclinically (53). Previously, both long‐acting and conventional G‐CSF supplementation was shown to be beneficial in mitigating liver cell apoptosis and intrahepatic fat accumulation (54). Perhaps a resistance to reduction, or conservation, of serum G‐CSF levels across treatment groups was protective in female offspring and supported healthier liver phenotypes.…”

Sheng‐Jiang Powder Ameliorates High Fat Diet Induced Nonalcoholic Fatty Liver Disease via Inhibiting Activation of Akt/mTOR/S6 Pathway in Rats

“…However, the role of Akt in the development of NAFLD is still controversial because of paradoxical results showed by different studies. Briefly, some studies found an obvious activation of sterol regulatory element binding protein 1c (SREBP-1c) followed by Akt activaiton, which promoted fat deposition in liver [ 14 ], while other studies revealed a distinct opposite role of Akt activation for protecting against hepatic steatosis [ 15 , 16 ]. Although no consistent view was achieved on this issue, it did indicate an important role of Akt in the pathogenesis of NAFLD at least.…”

The Current Status of Granulocyte-Colony Stimulating Factor to Treat Acute-on-Chronic Liver Failure

“…39,40 This effect might be, at least partly, immune cell-independent as hepatocytes also express the G-CSF receptor (csf3r). 41 In vitro exposure of HepG2 cells to saturated fatty acids decreased cell viability and increased csf3r expression. G-CSF treatment was associated with increasing cell proliferation, reduced reactive oxygen species production, and lipotoxicity.…”

“…41 G-CSF has been tested in various rodent models of liver injury (►Table 1), where it demonstrated pleiotropic effects, reducing fibrosis in models of chronic liver injury, 42 mitigating liver injury in models of acute liver failure, [43][44][45][46] activating liver progenitor cells after partial hepatectomy, 47 and reducing lipid accumulation and lipotoxicity in models of nonalcoholic fatty liver disease. 41,48 In rat models of acute liver failure, hematopoietic stem cells mobilized by G-CSF could be detected in liver tissue and were associated with a decrease in liver inflammation and an increase in hepatocyte mitotic activity, suggesting a positive effect on tissue repair. Untreated rodents had a low survival rate of 25% 18 hours after induction of acute liver failure but that rate increased to 60% (p < 0.001) with G-CSF.…”

“…Tsolaki et al42 CCl 4 induced chronic liver injury (mouse) G-CSF provides antifibrotic effect41 HF diet induced NAFLD (mouse) G-CSF reduced apoptosis and decreased hepatic lipid accumulationSong et al 48 HF diet induced NAFLD (rats) G-CSF reduced lipid accumulation and increased β-oxidation Abbreviations: CCl 4 , carbon tetrachloride; D-GalN, D-galactosamine; G-CSF, granulocyte-colony stimulating factor; HF, high fat; NAFLD, nonalcoholic fatty liver disease; TAA, thioacetamide. Seminars in Liver Disease Vol.…”