"Hypothesis of seven balances": molecular mechanisms behind alcoholic liver diseases and association with PPARalpha.

OBJECTIVES The purpose of this review to collate current leading scientific advances of molecular mechanisms in alcoholic liver diseases and to propose a working "hypothesis of seven balances" in relation to peroxisome proliferator activated receptor alpha (PPARalpha), which has important roles in fatty acid oxidation, oxidative stress, inflammatory responses, and possibly liver fibrosis. METHODS We conducted an extensive literature review of over a hundred publications and collated the findings with evidence generated in our laboratory. RESULTS Our research points to a working hypothesis of seven balances for alcoholic liver diseases consisting of: 1) ethanol oxidation balance in hepatocytes; 2) PPAR alpha activities in liver; 3) fatty acid metabolism balance in hepatic mitochondria; 4) gastrointestinal response to ethanol, acetaldehyde and lipopolysaccharide (LPS); 5) Kupffer cells response to LPS, oxidative stress and inflammatory cytokines; 6) adiponectin levels in plasma interchangeably regulated by tumor necrosis factor-alpha (TNF-alpha); and 7) stellate cells response to all of the above promoting hepatic fibrosis. Cellular mechanisms behind alcoholic liver diseases reveal close temporal associations of PPARalpha, adiponectin, TNF-alpha, cellular inflammation, proliferation, and potentially fibrosis as illustrated in "the hypothesis of seven balances." CONCLUSIONS The regulation and adjustment of PPARalpha activation underlying the balance of molecular cascades might resolve the progression of alcoholic liver diseases by reducing oxidative stress and inflammatory effects induced by nuclear factor-kappaB as well as the associated adiponectin pathway. Further elucidation of these pathways would reveal exciting new prospects for treating alcoholic liver diseases and other related liver disorders.