Hepatic disease

Over two million people in the UK suffer from a type of liver disease, with non-alcoholic fatty liver disease (NAFLD) being the most common liver disorder in developed countries. People are at an increased risk of developing NAFLD if they are obese, have Type 2 diabetes, or are over the age of 50. This project seeks to understand the underlying pathological mechanisms of NAFLD with a specific focus on diabetes- and age-related changes in hepatocyte function.

Diabetes

Methylglyoxal, a metabolite of glucose, is increased in Type 2 diabetics and may contribute to the complications associated with this disease.

The project aims included:
> Investigating the pathological role of methylglyoxal in hepatic disease
> Exploring possible interactions between methylglyoxal and free fatty acids on hepatocyte function

Age

We hypothesise that the age-related risk of developing NAFLD is due to increased methylglyoxal levels as the hepatic glyoxalase system, the methylglyoxal-metabolising enzyme, becomes impaired.

The project aims included:
> Determining the effect of age on liver glyoxalase expression and activity
> Investigating whether pharmacologically inhibiting glyoxalase enzymes in hepatocytes mimics the effect of age on cell function

> Methylglyoxal causes hepatocyte dysfunction and increases inflammation, both characteristics of NAFLD.
> Methylgyoxal and saturated fatty acids synergise in their dysfunctional-inducing effects on hepatocytes providing possible evidence of why Type 2 diabetics are at increased risk of developing NAFLD.
> Endogenous hydrogen sulphide, a gaseous transmitter found in mammals, can protect against methylglyoxal-mediated hepatocyte dysfunction.

Outputs

Ghela T, Mabley JG (2014). Exogenous and endogenous hydrogen sulfide protects the cardiomyocyte cell line H9c2 from methylglyoxal-mediated damage. Diabetologia 57(Suppl 1): S34-S34.

Walter TL, Mabley JG (2014). Synergistic hepatotoxic effects with a combination of methylglyoxal and palmitic acid. Diabetologia 57(Suppl. 1): S35-S35.

Tilliridou, V., A.A. Shamsabadi, H. Bergin, S. Al-Derzi, and J.G. Mabley, In vitro comparison of the hepatotoxic effects of efavirenz and etravirine on HepG2 cells. Hiv Medicine, 2013. 14: p. 25-25.

Loganathan, T., T. Buxton, and J. Mabley, In vitro determination of the hepatotoxic effects of methylglyoxal. Diabetologia, 2012. 55: p. S511-S511.