ABSTRACT
BACKGROUND: Colorectal cancer is a common malignancy and one of the leading causes of cancer-related deaths. The metabolism of omega fatty acids has been implicated in tumour growth and metastasis. METHODS: This study has characterised the expression of omega fatty acid metabolising enzymes CYP4A11, CYP4F11, CYP4V2 and CYP4Z1 using monoclonal antibodies we have developed. Immunohistochemistry was performed on a tissue microarray containing 650 primary colorectal cancers, 285 lymph node metastasis and 50 normal colonic mucosa. RESULTS: The differential expression of CYP4A11 and CYP4F11 showed a strong association with survival in both the whole patient cohort (hazard ratio (HR)=1.203, 95% CI=1.092-1.324, χ2=14.968, P=0.001) and in mismatch repair-proficient tumours (HR=1.276, 95% CI=1.095-1.488, χ2=9.988, P=0.007). Multivariate analysis revealed that the differential expression of CYP4A11 and CYP4F11 was independently prognostic in both the whole patient cohort (P=0.019) and in mismatch repair proficient tumours (P=0.046). CONCLUSIONS: A significant and independent association has been identified between overall survival and the differential expression of CYP4A11 and CYP4F11 in the whole patient cohort and in mismatch repair-proficient tumours.
Subject(s)
Colorectal Neoplasms/chemistry , Colorectal Neoplasms/enzymology , Cytochrome P-450 CYP4A/analysis , Cytochrome P450 Family 4/analysis , Aged , Colon/chemistry , Colorectal Neoplasms/pathology , DNA Mismatch Repair , Fatty Acids, Omega-3/metabolism , Fatty Acids, Omega-6/metabolism , Female , Humans , Intestinal Mucosa/chemistry , Lymphatic Metastasis , Male , Prognosis , Survival RateABSTRACT
The ligand-dependent transcription factor peroxisome proliferator-activated receptor alpha (PPARalpha) is known to be activated by common fatty acids and to regulate the expression of genes of various lipid oxidation pathways and transport. High-fat diets provide more fatty acids, which presumably could enhance lipid catabolism through up-regulation of PPARalpha signaling. However, high intake of fat could also lead to obesity. To examine PPARalpha signaling in high-fat feeding and obesity, this study examined the hepatic mRNA expression of PPARalpha and some of its target genes in Wistar rats and C57BL/6J mice fed two levels (20% or 30% wt/wt) of high-safflower-oil (SFO; oleic-acid-rich) diets until animals showed significantly higher body weight (13 weeks for rats and 22 weeks for mice) than those of control groups fed a 5% SFO diet. At the end of these respective feeding periods, only the rats fed 30% SFO and the mice fed 20% SFO among the two groups fed high-fat diets showed significantly higher body weight, white adipose tissue weight, serum leptin and mRNA expression of PPARalpha (P<.05) compared to the respective control groups. Despite elevated acyl-CoA (a PPARalpha target gene) protein and activity in both groups fed high-fat diets, the mRNA expression level of most PPARalpha target genes examined correlated mainly to PPARalpha mRNA levels and not to fat intake or liver lipid levels. The observation that the liver PPARalpha mRNA expression in groups fed high-fat diets was significantly higher only in obese animals with elevated serum leptin implied that obesity and associated hyperleptinemia might have a stronger impact than dietary SFO intake per se on PPARalpha-regulated mRNA expression in the liver.
Subject(s)
Adiposity/genetics , Leptin/blood , Liver/chemistry , PPAR gamma/genetics , RNA, Messenger/analysis , Safflower Oil/administration & dosage , Acyl-CoA Oxidase/analysis , Acyl-CoA Oxidase/genetics , Acyl-CoA Oxidase/metabolism , Adipose Tissue/anatomy & histology , Animals , Body Weight , Cytochrome P-450 CYP4A/analysis , Dietary Fats, Unsaturated/administration & dosage , Eating , Fatty Acids, Nonesterified/analysis , Fatty Acids, Nonesterified/blood , Gene Expression Regulation , Lipids/analysis , Lipids/blood , Liver/enzymology , Male , Mice , Mice, Inbred C57BL , Obesity/blood , Organ Size , Rats , Rats, Wistar , Triglycerides/analysis , Triglycerides/bloodABSTRACT
Rats fed a saturated fat diet are protected from experimentally induced alcoholic liver disease, but the molecular mechanisms underlying this phenomenon remain in dispute. We fed male Sprague-Dawley rats intragastrically by total enteral nutrition using diets with or without ethanol. In 1 control and 1 ethanol group, the dietary fat was corn oil at a level of 45% of total energy. In other groups, saturated fat [18:82 ratio of beef tallow:medium-chain triglyceride (MCT) oil] was substituted for corn oil at levels of 10, 20, and 30% of total energy, while keeping the total energy from fat at 45%. After 70 d, liver pathology, serum alanine aminotransferase (ALT), biochemical markers of oxidative stress, liver fatty acid composition, cytochrome P450 2E1 (CYP2E1) expression and activity and cytochrome P450 4A (CYP4A) expression were assessed. In rats fed the corn oil plus ethanol diet, hepatotoxicity was accompanied by oxidative stress. As dietary saturated fat content increased, all measures of hepatic pathology and oxidative stress were progressively reduced, including steatosis (P < 0.05). Thus, saturated fat protected rats from alcoholic liver disease in a dose-responsive fashion. Changes in dietary fat composition did not alter ethanol metabolism or CYP2E1 induction, but hepatic CYP4A levels increased markedly in rats fed the saturated fat diet. Dietary saturated fat also decreased liver triglyceride, PUFA, and total FFA concentrations (P < 0.05). Increases in dietary saturated fat increased liver membrane resistance to oxidative stress. In addition, reduced alcoholic steatosis was associated with reduced fatty acid synthesis in combination with increased CYP4A-catalyzed fatty acid oxidation and effects on lipid export. These findings may be important in the nutritional management and treatment of alcoholic liver disease.