Metabolic effects of hypoxia and chronic hepatitis C

Lim, Teegan Reina (2018). Metabolic effects of hypoxia and chronic hepatitis C. University of Birmingham. Ph.D.

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Abstract

Hypoxia has been linked to the pathogenesis of hepatic steatosis in murine and human models. There is an abundance of data suggesting that HIFs play a central role in regulating hepatic lipid metabolism. This study suggested that hypoxia-induced hepatic lipid accumulation is through de novo lipogenesis and free fatty acid uptake, and is dependent on hypoxia inducible factors la and 2a. On the contrary, hepatitis C infection reduced de novo lipogenesis and free fatty acid uptake in both normoxic and hypoxic conditions in vitro, and this inhibition is viral strain-dependent. In the clinical setting, chronic hepatitis C {CHC) and non-alcoholic fatty liver diseases {NAFLD) are associated with hepatic steatosis and insulin resistance. Using an integrative physiological approach that measures lipid and carbohydrate flux in vivo we demonstrated that patients with CHC had modest increase in insulin resistance and that the relative contribution of tissue specific insulin sensitivity in patients with CHC and NASH varied. Furthermore, curing HCV infection improved hepatic and subcutaneous adipose tissue insulin resistance. The improvement in hepatic and adipose tissue insulin resistance was more pronounced in patients infected with genotype 3 HCV, whilst the improvement in skeletal muscle insulin resistance was more evident in genotype 1 infection, demonstrating a genotype-specific effect in the metabolic perturbation in CHC. Further studies are required to confirm that genotype specific effect of HCV on insulin resistance and its link with NASH.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

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