Hepatic gene expression in morbidly obese women: implications for disease susceptibility.

The objective of this study was to determine the molecular bases of disordered hepatic function and disease susceptibility in obesity. We compared global gene expression in liver biopsies from morbidly obese (MO) women undergoing gastric bypass (GBP) surgery with that of women undergoing ventral hernia repair who had experienced massive weight loss (MWL) following prior GBP. Metabolic and hormonal profiles were examined in MO vs. MWL groups. Additionally, we analyzed individual profiles of hepatic gene expression in liver biopsy specimens obtained from MO and MWL subjects. All patients underwent preoperative metabolic profiling. RNAs were extracted from wedge biopsies of livers from MO and MWL subjects, and analysis of mRNA expression was carried out using Affymetrix HG-U133A microarray gene chips. Genes exhibiting greater than twofold differential expression between MO and MWL subjects were organized according to gene ontology and hierarchical clustering, and expression of key genes exhibiting differential regulation was quantified by real-time-polymerase chain reaction (RT-PCR). We discovered 154 genes to be differentially expressed in livers of MWL and MO subjects. A total of 28 candidate disease susceptibility genes were identified that encoded proteins regulating lipid and energy homeostasis (PLIN, ENO3, ELOVL2, APOF, LEPR, IGFBP1, DDIT4), signal transduction (MAP2K6, SOCS-2), postinflammatory tissue repair (HLA-DQB1, SPP1, P4HA1, LUM), bile acid transport (SULT2A, ABCB11), and metabolism of xenobiotics (GSTT2, CYP1A1). Using gene expression profiling, we have identified novel candidate disease susceptibility genes whose expression is altered in livers of MO subjects. The significance of altered expression of these genes to obesity-related disease is discussed.

Effect of combination lipid-modifying therapy on the triglyceride lowering effect of fish oil.

BACKGROUND: Marine fish oil supplements are frequently administered with other lipid medications for treatment of hypertriglyceridemia. The efficacy of fish oil may be reduced in the presence of other lipid agents, particularly fibrates that also act as PPARalpha agonists. We therefore sought to determine the efficacy of fish-oil supplements when coadministered with other lipid-modifying agents. METHODS: Patients receiving fish oil supplements were identified from the computer database of a large governmental HMO. Change in plasma lipoprotein levels after administration of fish oil was compared between patients receiving fish oil as their only treatment and those for whom fish oil was added to other drugs. RESULTS: A total of 166 evaluable records were identified, 66 from patients treated with fish oil alone and 100 from patients for whom fish oil was added to another agent or other agents. Fish oil effectively reduced triglyceride levels to an equal extent in the fish oil only and fish oil added groups (-30% versus -27% respectively; P = 0.84). CONCLUSION: Fish oil effectively reduces plasma triglyceride levels when administered with concomitant lipid medications. These findings suggest the presence of additional and even complementary mechanisms of action of fish oil to lower triglyceride when added to other lipid drugs. These findings validate the common clinical practice of combining fish oil supplements with other lipid-lowering medications in patients with hypertriglyceridemia.