Non-Alcoholic Fatty Liver Disease (NAFLD), or steatosis, is characterised by fat accumulation in hepatocytes in the liver where accumulation exceeds 5% of the volume or weight, independent of excessive alcohol consumption. The most prevalent liver disease was found to be NAFLD which affects an estimated 5.5 million Australians, including 40% of all adults aged 50 years and above. Moreover, the health costs of treating liver disease in 2012 were estimated as $432 million. NAFLD is more common in the presence of diabetes, obesity, hypercholesterolemia and increased inflammation, and is more likely to progress to cirrhosis and liver failure. Unfortunately mechanism of metabolic syndrome-derived NAFLD is not well understood and no specific therapy exists.
We have previously shown that interleukin 22 (IL-22) is a natural regulator of insulin biosynthesis and secretion, protecting the β-cell from stress and controlling hyperglycaemia in mice 1. The IL-22 receptor (IL-22RA1) is very highly expressed on hepatocytes. Therefore, in the current study we tested the whether IL-22 targets hepatocytes and suppresses oxidative/ER stress to restore metabolic function in murine models of NAFLD.
In HFD induced NAFLD mice IL-22 (i) restore enzymatic activity of liver (ii) increased the activation of cholesterol regulatory signalling effectors in liver to efflux excess lipid from the liver, (iii) induced ~5% of liver weight and body weight loss over the 4 weeks of treatment, (iv) protected hepatocyte from oxidative stress and (v) effectively restored glycaemic control within 10 days of commencement of treatment.
Together these results demonstrate that IL-22-based therapy preserves biological activity of liver, decreases liver fat accumulation and induces cholesterol regulatory signalling which draw liver specific effect of IL-22 and the evidence that targeting can be used to reduce IL-22 effects on other tissues such as gut and skin while maintaining protective metabolic effects.