Bariatric surgery-induced weight loss reduces hepatic lipid peroxidation levels and affects hepatic cytochrome P-450 protein content.

Nonalcoholic fatty liver disease (NAFLD) has become one of the most common liver diseases in developed countries. Fatty liver encompasses an entire spectrum of disease, from accumulation of lipid (simple steatosis) to the more progressive nonalcoholic steatohepatitis (NASH) associated with fibrosis, necrosis, inflammation, and ultimately cirrhosis. As obesity and metabolic syndrome are both strongly associated with NAFLD, a logical therapeutic avenue for the treatment of fatty liver is weight loss. Indeed, it has been demonstrated that weight loss following bariatric surgery results in significant improvement in features of NAFLD and metabolic syndrome as well as normalization of liver histology.1–5 Although surgical-induced weight loss can effectively improve liver histology in NAFLD, the pathogenesis of NAFLD and NASH is not well understood. One hypothesis is that oxidative stress and inflammation, leading to increased lipid peroxidation, may play a central role in the development of NASH. It has been shown that levels of lipid peroxidation are increased in human NASH6–9 and suggested that the pro-inflammatory and pro-fibrotic aldehyde end products of lipid peroxidation (malondialdehyde [MDA] and 4-hydroxynonenal) can potentially account for all of the histologic features observed in NASH.10 For example, compared with liver tissue from normal individuals and patients with NAFLD, liver tissue from NASH patients demonstrates elevated markers of lipid peroxidation,7 and there is a significant correlation between hepatic lipid peroxidation levels and hepatic fibrosis in patients across the spectrum of NAFLD.9 One important source of lipid peroxidation and oxidative stress in the liver is cytochrome P-450 2E1 (CYP2E1), a microsomal enzyme involved in fatty acid hydroxylation that is capable of initiating the process of lipid peroxidation which may be important in the pathogenesis of NASH. Expression and activity of CYP2E1 is increased in human NAFLD and NASH11–14 and in animal models of NASH.15,16 Although the exact role of CYP2E1 in the pathogenesis of NAFLD and NASH is unclear, it is known that CYP2E1 can undergo futile cycling in the absence of substrates and is therefore capable of producing large amounts of reactive oxygen species, including superoxide anions, hydroxyl radicals, and hydrogen peroxides that can induce cellular injury and/or death.6 Mechanistic studies have demonstrated a direct link between increased CYP2E1 activity and hepatocyte injury that operates through a pathway involving oxidative stress. This is evidenced by both induction of CYP2E1 with pharmacological agents and overexpression of CYP2E1 producing heightened sensitivity and increased cell death in response to ethanol and fatty acids, and the ability of both CYP2E1 inhibitors and antioxidants to block apoptosis induced by these agents.17,18 Although alterations in lipid peroxidation levels and CYP2E1 expression and activity in human NAFLD and NASH have been characterized, little information is available regarding other important CYP enzymes in liver disease and drug metabolism, such as the CYP3A subfamily. CYP3A (including the CYP3A4, CYP3A5, fetal CYP3A7, and CYP3A43 isoforms) is the most abundant CYP in the human body and is responsible for the metabolism of more than 50% of drugs that are currently available.19,20 A representative list of medications that are metabolized by the CYP3A family and CYP2E1 is shown in Table 1. In general, chronic liver diseases such as cirrhosis are associated with decreased clearance of drugs, including several substrates of CYP3A.21 This is attributed to both decreased blood flow to hepatocytes as well as decreased functional capacity of hepatocytes. Although examination of CYP3A activity and expression in NAFLD and NASH is very limited, Weltman et al reported a decrease in CYP3A immunostaining in liver sections from patients with NASH compared with healthy controls12 and Leclercq et al have shown that in a nutritionally-induced animal model of hepatic steatosis, lipid accumulation was accompanied by a significant reduction in both CYP3A protein expression and activity.22 In humans, we recently demonstrated that steatosis is associated with a significant reduction in hepatic CYP3A activity in vitro, but that CYP3A protein expression is unchanged.23 Additional studies are clearly needed to further characterize hepatic CYP3A protein expression and activity in humans with fatty liver disease. TABLE 1 Medications Metabolized by CYP3A and CYP2E1 In the current study, we measured levels of hepatic lipid peroxidation and CYP2E1 and CYP3A protein expression and distribution before and after bariatric surgery-induced weight loss. In this longitudinal study, we also considered patient clinical characteristics (including measures of fatty liver disease and metabolic syndrome), histologic findings, serum parameters, and patient comorbidities and demographics for correlative studies within our well-characterized group of patients.