Altered Fgf21 response in alcohol induced “Acute-on-chronic liver injury” (ACLI) model

Karataylı, Ersin; Christidis, Grigorios; Hall, R; Weber, SN; Dooley, Steven; Lammert, Frank; Karatayli, SC

doi:10.1055/s-0038-1677084

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“…Given that FGF21 resistance is characterized by increased levels of circulating FGF21 levels concomitant with decreased FGF21 receptor expression (33)(34)(35), these findings suggest that our ethanol treatments produced a state of FGF21 resistance. Meanwhile, our GSIS, cell death rate, and cell viability data showing that short-term ethanol exposure did not impair β-cell function or survival support the hypothesis that FGF21 may protect pancreatic islets from ethanol-induced pancreatic islet damage similar to the way that it has been shown to be protective against ethanol-induced hepatic damage and the progression of alcoholic liver disease in an acute alcohol drinking model (36)(37)(38).…”

Section: Discussionsupporting

confidence: 75%

Alcohol ingestion induces pancreatic islet dysfunction and apoptosis via mediation of FGF21 resistance

Yang

Leung

2020

Ann Transl Med

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Background: Disruption of β-cell insulin secretion and viability caused by excessive ethanol consumption increases type 2 diabetes mellitus (T2DM) pathogenesis risk. Fibroblast growth factor 21 (FGF21) plays a significant role in regulating lipid and glucose homeostasis. Recently, FGF21, best known for its role in lipid and glucose homeostasis regulation, and its obligate co-receptor β-klotho have been shown to inhibit ethanol ingestion and metabolism. It remains unclear whether heavy ethanol intake modulates islet FGF21 expression and function. This study investigated the relationship between ethanol exposure, FGF21, and islet function in vivo/ex vivo islet and in vitro cell models.Methods: Mice were gavaged with 3.5 g/kg ethanol or saline for 1-3 weeks (long-term exposure). Human MIN6 cells and isolated islets were cultured and treated with 80 mM ethanol for 24 h (short-term exposure) to mimic excessive ethanol consumption. We applied the oral glucose tolerance test (OGTT), blood glucometry, enzyme-linked immunosorbent assay (ELISAs) for insulin and FGF21, glucose stimulated insulin secretion (GSIS) testing, reverse-transcription (RT)-polymerase chain reaction (PCR), and western blot experiments.Results: Long-term ethanol treatment induced FGF21 resistance in mouse pancreatic islets. Moreover, ethanol exposure damaged insulin secretory ability and glucose homeostasis. In vitro and ex vivo experiments showed that short-term ethanol treatment upregulated the expression of FGF21 signaling pathway-related genes and proteins, without affecting β-cell survival or function.Conclusions: Long-term ethanol consumption induces FGF21 resistance-mediated pancreatic β-cell dysfunction, and thus diabetes pathogenesis risk.

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