Fibroblast growth factor (FGF)-21 based therapies: A magic bullet for nonalcoholic fatty liver disease (NAFLD)?

Doxepin Exacerbates Renal Damage, Glucose Intolerance, Nonalcoholic Fatty Liver Disease, and Urinary Chromium Loss in Obese Mice

“…Our results regarding the body weight and fatty liver score increases after doxepin treatment in obese mice are potentially attributable to the reduction in the serum levels of FGF-21, which attenuated protection against NAFLD (including nonalcoholic fatty liver and nonalcoholic steatohepatitis) [ 40 , 52 ]. Furthermore, our results that doxepin treatment increased serum ALT and AST levels accords with the inability of FGF-21 to reduce the increased lipid accumulation in hepatocytes, resulting in lipid-overload stress and the subsequent release of multiple proinflammatory factors such as tumor necrosis factor (TNF) α and C-reactive protein (CRP) [ 51 , 53 ]—all leading to chronic low-grade liver inflammatory status. In addition, PNPLA3 may promote liver inflammation during NAFLD progression by increasing TNF-α expression and activating the endoplasmic reticulum stress-mediated and NF-κB–independent inflammatory inositol–requiring enzyme-1α/c-Jun amino-terminal kinase pathway [ 54 ].…”

“…Similarly, some studies have reported the occurrence of liver abnormalities, including aminotransferase abnormalities and cholestatic hepatitis, after tricyclic antidepressant treatment in patients [ 49 , 50 ]. In addition, a pharmacological report linked higher serotonin levels promote liver lipid accumulation and liver steatosis development [ 51 ]. These findings corroborate our results for doxepin-treated mice regarding the large increases in WAT and liver weights, serum and liver triglycerides levels, and fatty liver scores in response to increased serum serotonin levels ( Figure S4 ).…”

“…Compared with the saline-treated control mice, the mice receiving doxepin had increased fatty liver scores—possibly because doxepin reduced the activity of fibroblast growth factor (FGF)-21 ( Figure S5 ), the physiological energy sensor associated with fat and glucose metabolism through the promotion of mitochondrial oxidative capacity and peroxisome proliferator–activated receptor-γ activity. FGF-21 can have implications for viable therapeutic strategies to reduce body weight and increase energy expenditure as well as stop or undo liver fibrosis, inflammation, and fat infiltration by increasing adiponectin secretion to inhibit the nuclear factor κB inflammatory signaling pathway [ 51 , 52 ]. Our results regarding the body weight and fatty liver score increases after doxepin treatment in obese mice are potentially attributable to the reduction in the serum levels of FGF-21, which attenuated protection against NAFLD (including nonalcoholic fatty liver and nonalcoholic steatohepatitis) [ 40 , 52 ].…”

Advances of Fibroblast Growth Factor/Receptor Signaling Pathway in Hepatocellular Carcinoma and its Pharmacotherapeutic Targets

“…However, only FGF19 activates FGFR4 in vitro. The abundant expression of ß-klotho in the liver indicates that FGF15/19 and FGF21 act in the liver, which has been confirmed by multiple studies (Kharitonenkov et al, 2008;Yang et al, 2012a;Ding et al, 2012;Schumann et al, 2016;Agrawal et al, 2018;Ritchie et al, 2020). FGF19 is involved in postprandial gut-liver communications and acts as a growth factor for hepatocytes as well as hepatic bile acid synthesis (Kir et al, 2011).…”

“…FGF21 is now considered as a key regulator of stress response in humans (Luo et al, 2017;Wu et al, 2017). Under stress conditions, elevated circulating FGF21 levels mostly appear to be derived from the liver, which has been confirmed in a series of liver-related disease models, such as liver inflammation; liver injury elicited by ethanol, drugs, or ischemia/reperfusion; liver regeneration; and hepatocarcinogenesis (Yang et al, 2013a;Ye et al, 2014;Ye et al, 2016;Desai et al, 2017;Wu et al, 2017;Ritchie et al, 2020). Taken together, the liver is recognized as a major direct or indirect target organ for FGF15/19 and FGF21 because of their expression in the liver with physiological and pathological conditions.…”