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

Abstract

Objective: To evaluate the effects of surgical weight loss on hepatic lipid peroxidation levels and cytochrome P-450 protein expression in patients with nonalcoholic fatty liver disease (NAFLD).

Summary background data: NAFLD and nonalcoholic steatohepatitis (NASH) affect hepatic cytochrome P-450 (CYP) protein expression and activity, and CYP2E1 may play a role in the pathogenesis of NAFLD and NASH through induction of oxidative stress and lipid peroxidation. NAFLD and NASH are associated with increased systemic lipid peroxidation levels and elevated hepatic CYP2E1 activity, but hepatic CYP3A4/5 activity is decreased.

Methods: Liver biopsies from 20 patients with NAFLD who underwent bariatric surgery were obtained intraoperatively and at 15 +/- 7 months following surgery. Hepatic malondialdehyde (MDA) levels (a marker of lipid peroxidation), CYP2E1 and CYP3A4/5 protein expression, and steatosis, as a percent of total area, were measured by immunohistochemistry followed by digital image quantitation.

Results: Following weight loss, as reflected by reduced BMI (54 +/- 9 vs. 37 +/- 9 kg/m2; P < 0.001), features of the metabolic syndrome, grade and stage of liver disease, and liver histology were all significantly improved (P < 0.01). Hepatic MDA staining (35 +/- 18% vs. 23 +/- 14%; P = 0.02), CYP2E1 protein content (68 +/- 9% vs. 56 +/- 11%; P < 0.001), and steatosis (17 +/- 7% vs. 2 +/- 3%; P < 0.001) were significantly reduced following weight loss. CYP3A4/5 protein content was unchanged (57 +/- 13% vs. 55 +/- 13%; P = 0.433). The reduction in lipid peroxidation was independently associated with changes in CYP2E1 protein expression after bariatric surgery (r = 0.477; P = 0.033).

Conclusion: Elevations in hepatic lipid peroxidation and CYP2E1 expression that are seen in NAFLD improve significantly with weight loss induced by bariatric surgery.

FIGURE 1

Immunohistochemical staining of liver biopsies before and after bariatric surgery. Lipid peroxidation levels (measured by malondialdehyde [MDA] staining) are greater prior to bariatric surgery (Panel A) and are significantly reduced following weight loss (Panel B). Prior to surgery (Panel C), there is extensive steatosis surrounded by intense CYP2E1 staining. Following surgery and weight loss (Panel D), CYP2E1 protein expression is significantly decreased. CYP3A4/5 protein content is unchanged following bariatric surgery (compare Panels E and F), despite the improvements in liver histology and steatosis after weight loss.

FIGURE 2

Changes in hepatic lipid peroxidation levels following weight loss are independently associated with changes in CYP2E1 protein expression (r = 0.477; P = 0.033). Lipid peroxidation levels (measured by malondialdehyde [MDA] staining) and CYP2E1 protein content was measured in liver biopsies taken before and after weight loss by immunohistochemistry followed by digital image quantification and is represented as the percent (%) of the total liver biopsy area that stained positive for MDA or CYP2E1.

FIGURE 3

Changes in hepatic CYP2E1 protein expression following weight loss are independently associated with resolution of dyslipidemia (P = 0.013). CYP2E1 protein content was measured in liver biopsies by immunohistochemistry followed by digital image quantification and is represented as the percent (%) of the total liver biopsy area that stained positive for CYP2E1. Of the 20 subjects who participated in the study, 18 had dyslipidemia prior to bariatric surgery. After weight loss, resolution of dyslipidemia was observed in 13 patients (72%) but remained in 5 subjects (28%).

FIGURE 4

Baseline hepatic CYP3A4/5 protein expression is independently associated with hepatic CYP2E1 protein content prior to bariatric surgery and weight loss (r = 0.564; P = 0.010). Hepatic CYP protein content was measured by immunohistochemistry followed by digital image quantitation of protein expression in 20 subjects before and after bariatric surgery-induced weight loss. CYP protein expression is represented as the percent (%) of the total liver biopsy area that stained positive for the CYP protein of interest.