Date on Master's Thesis/Doctoral Dissertation
Pharmacology and Toxicology
Arteel, Gavin Edward
Liver disease; Alcoholic liver disease; Steatosis; Fibrosis
Protein kinases; Liver--Diseases
Alcoholic liver disease (ALD) is a serious concern for the world's population. It is one of the leading causes of death and is also a huge economic burden. The biochemical mechanisms responsible for ALD are incompletely understood, therefore there is no FDA approved therapy to treat or reverse liver damage caused by alcohol exposure. Whereas the mechanisms behind ALD are poorly understood, the disease progression is well known. The first pathological step of ALD is steatosis followed by inflammation and necrosis; if the insult(s) responsible for the previous pathologies persists, fibrosis and cirrhosis can then develop. In previous experimental studies, preventing alcohol-induced steatosis can protect against further stages of liver damage; thus, understanding the mechanisms responsible for ethanol-induced steatosis may result in a therapy to treat ALD. Previous studies have shown that protein kinase-c epsilon (PKC[varepsilon]) contributes to steatosis owing to a non-alcoholic high fat diet. However, the role of PKC[varepsilon] in alcohol-induced fatty liver is not yet known. Therefore, the goal of this work was to investigate the role of PKC[varepsilon] in not only steatosis, but also in later stages of liver disease (i.e. steatohepatitis and fibrosis). It was determined in both acute and chronic mouse models of ethanol exposure that PKC[varepsilon] plays a causal role in steatosis owing to ethanol. Surprisingly, blocking steatosis had no apparent protective effect on inflammation and necrosis in the chronic model, which implies that these pathologies may have mechanistic distinctions. Lastly, it was shown that PKC[varepsilon] plays a pivotal role in the development of fibrosis caused by chronic exposure to carbon tetrachloride (CCl 4 ). In summary, it appears that PKC[varepsilon] plays a causal role in the early (steatosis) and late (fibrosis) stages of liver disease. The inhibition of PKC[varepsilon] could therefore result in a viable therapeutic means of preventing ALD.
Kaiser, J. Phillip 1981-, "The role of PKC-epsilon in models of alcohol- and toxin-induced liver disease." (2009). Electronic Theses and Dissertations. Paper 720.