Hypercholesterolemia and changes in lipid and bile acid metabolism in male and female cyp7A1-deficient mice

Abstract

Cholesterol 7 ␣ -hydroxylase, a rate-limiting enzyme for bile acid synthesis, has been implicated in genetic susceptibility to atherosclerosis. The gene, CYP7A1 , encoding a protein with this activity, is expressed normally only in hepatocytes and is highly regulated. Our cyp7A1 gene knockout mouse colony, as young adults on a chow diet, is hypercholesterolemic. These mice were characterized extensively to understand how cyp7A1 affects lipid and bile acid homeostasis in different tissue compartments and whether gender plays a modifying role. Both male and female cyp7A1-deficient mice had decreased hepatic LDL receptors, unchanged hepatic cholesterol synthesis, increased intestinal cholesterol synthesis and bile acid transporters, and decreased fecal bile acids but increased fecal sterols. In females, cyp7A1 deficiency also caused changes in hepatic fatty acid metabolism, decreased hepatic canalicular bile acid transporter, Bsep, and gallbladder bile composition altered to a lithogenic profile. Taken together, the data suggest that cyp7A1 deficiency results in a proatherogenic phenotype in both genders and leads to a prolithogenic phenotype in females.

Bile Acid Signaling Is Involved in the Neurological Decline in a Murine Model of Acute Liver Failure

“…As mentioned above, these mice had a reduced total bile acid pool and fecal bile acid content, but a significant reduction in certain bile acids, such as DCA, lithocholic acid, and b-muricholic acid. 16 Furthermore, our data suggest that feeding mice with diets enriched with either cholic acid or DCA increased the susceptibility of these mice to the development of HE. DCA-fed mice that were administered AOM had worse neurological decline but exhibited less cerebral edema compared with mice administered AOM and were fed a control diet.…”

“…Cyp7A1 À/À mice have previously been shown to have reduced fecal bile acid content and total bile acid pool, as well as reduced concentrations of DCA, lithocholic acid, and b-muricholic acid. 16 Reduced circulating bile acid content was confirmed in Cyp7A1 À/À compared with WT controls ( Figure 3A). Treatment of Cyp7A1 À/À mice with AOM demonstrated significantly delayed neurological decline ( Figure 3B) and increased time to coma ( Figure 3C) compared with WT mice.…”

“…Breeding pairs of Cyp7A1 heterozygous knockout mice were a kind gift from Dr. Sandra Erickson (University of California, San Francisco, CA). 16 Cyp7A1 heterozygous knockout mice were bred on a C57Bl/6 background to establish a breeding colony. Homozygous Cyp7A1 knockout mice (Cyp7A1 À/À ) and wild-type (WT) littermates were used in all experiments.…”

Interaction between Altered Insulin and Lipid Metabolism in CEACAM1-inactive Transgenic Mice

“…Fatty Acid Synthesis in Vivo-Synthesis of fatty acids was determined in vivo by the 3 HOH method in 7-month-old nonfasted mice at 1400 -1500 h (34).…”

Nutrigenomics of hepatic steatosis in a feline model: effect of monosodium glutamate, fructose, and Trans-fat feeding

“…A total of 38 genes were represented in the network, with a number of focus genes with functions relating to transcription, growth and proliferation, and lipid metabolism lipid profile while consuming a diet enriched for Trans-fat/ HFCS is provided by the fact that the expression of lipogenic genes such as FAS and ACLY, together with major lipogenic transcription factor SREBP1C (Guillou et al 2008), were robustly downregulated in the livers of these animals. We also noted that the expression of genes involved in bile acid synthesis and efflux (Erickson et al 2003) for example Cyp7a1, ABCG8, ABCC3/MRP3, cholesterol uptake (LDLR), transport (ApoB), and de novo cholesterol synthesis (HMGCR, HMGCS1) were all reduced in cats fed the Trans-fat/HFCS diet, and this may explain why these cats did not exhibit increased levels of serum cholesterol and hepatic TAG compared to control.…”