Fatty acid binding protein 4 in obesity related liver disease; from steatosis to cancer progression
| Autor: | Iain McKillop, Neha Attal, Emilio Marrero, Kyle Thompson |
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| Rok vydání: | 2023 |
| Předmět: | |
| Zdroj: | Physiology. 38 |
| ISSN: | 1548-9221 1548-9213 |
| Popis: | Background. In healthy individuals hepatic lipid transport and storage is closely regulated via several integrated pathways, including a central role for fatty acid binding protein-1 (FABP1). Increased hepatic fat accumulation (non-alcoholic fatty liver disease [NAFLD]) in patients with obesity is a common pathology that, if left unchecked, increases the risk of progression toward non-alcoholic steatosis (NASH) and hepatocellular carcinoma (HCC). Despite increased fat accumulation in NAFLD, FABP1 levels are unchanged in the liver. We hypothesized that a gene analysis array would reveal expression of alternative pathways in NAFLD-NASH associated with the progressive worsening of liver health in the setting of obesity. Methods. Using a high fat diet (HFD) mouse model of obesity and control (normal diet) mice a gene array analysis was performed on liver tissue. This approach revealed high levels of FABP4 mRNA expression (an FABP form normally expressed in adipocytes and macrophages) in HFD liver tissue. Subsequent mRNA (qRT-PCR) and protein (ELISA, Western blot, immunohistochemistry) analysis was performed in serum and tissue from obese mouse models and human samples. Using in vitro models, the effect of free fatty acids (FFAs) on FABP4 mRNA expression and protein synthesis/secretion was analyzed. Finally, the effect of exogenous rhFABP4 on hepatoma cell activity was determined in the presence/absence of pharmacological inhibitors. Results. FABP1 mRNA expression was not significantly altered in HFD liver tissue from clinical samples from patients with obesity and rodent samples compared to normal liver. Conversely, FABP4 mRNA and protein expression was significantly elevated in tissue and serum samples from HFD liver tissue. Using in vitro models, significant increases in FABP4 mRNA expression was detected in the presence of FFAs, and de novo FABP4 protein was secreted into culture medium. Exogenous rhFABP4 stimulated hepatoma cell proliferation and migration in vitro in a concentration-dependent manner. Analysis of intracellular signaling pathways (in the presence/absence of inhibitors) demonstrated rhFABP4 stimulated proliferation and migration via increased ERK and JNK activity, but not via p38MAPK signaling. Lastly, using an inhibitor that targets the FFA binding pocket of FABP4 (BMS 309403) we demonstrated inhibition of FFA binding does not inhibit the effect of rhFABP4 on ERK or JNK signaling or hepatoma proliferation and migration. Conclusions. Obesity fails to alter hepatic expression of FABP1 but leads to increased FABP4 mRNA expression and protein secretion in vitro and in vivo. Using in vitro models, rhFABP4 stimulates hepatoma cell proliferation and migration, suggesting FABP4 released from steatotic hepatocytes may act in a paracrine/endocrine manner to stimulate foci expansion and/or tumor progression in vivo. Future studies aim to identify novel FABP4 antagonists that inhibit FABP4-de NIH Grant# AA029241-01 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process. |
| Databáze: | OpenAIRE |
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