Effect of dietary cholesterol and taurocholate on cholesterol 7 alpha-hydroxylase and hepatic LDL receptors in inbred mice

There is no consensus whether hepatic lipid regulatory enzymes play primary or secondary roles in cholesterol cholelithiasis. We have used inbred mice with Lith genes that determine cholesterol gallstone susceptibility to evaluate the question. We studied activities of regulatory enzymes in cholesterol biosynthesis (HMG-CoA reductase), cholesterol esterification (acyl-CoA:cholesterol acyltransferase) and the "neutral" (cholesterol 7 ␣ -hydroxylase) and "acidic" (sterol 27-hydroxylase) pathways of bile salt synthesis in strains C57L/J and SWR/J as well as recombinant inbred (AKXL-29) mice, all of which have susceptible Lith alleles, and compared them to AKR/J mice with resistant Lith alleles. We determined hepatic enzyme activities of male mice before and at frequent intervals during feeding a lithogenic diet (15% dairy fat, 1% cholesterol, 0.5% cholic acid) for 12 weeks. Basal activities on chow show significant genetic variations for HMG-CoA reductase, sterol 27hydroxylase, and acyl-CoA: cholesterol acyltranferase, but not for cholesterol 7 ␣ -hydroxylase. In response to the lithogenic diet, activities of the regulatory enzymes in the two bile salt synthetic pathways are coordinately down-regulated and correlate inversely with prevalence rates of cholesterol crystals and gallstones. Compared with gallstone-resistant mice, significantly higher HMG-CoA reductase activities together with lower activities of both bile salt synthetic enzymes are hallmarks of the enzymatic phenotype in mice with susceptible Lith alleles. The most parsimonious explanation for the multiple enzymatic alterations is that the primary Lith phenotype induces secondary events to increase availability of cholesterol to supply the sterol to the hepatocyte canalicular membrane for hypersecretion into bile. -Lammert, F., D. Q-H. Wang, B. Paigen, and M. C. Carey. Phenotypic characterization of Lith genes that determine susceptibility to cholesterol cholelithiasis in inbred mice: integrated activities of hepatic lipid regulatory enzymes.

Section: Discussionsupporting

confidence: 82%

Phenotypic characterization of Lith genes that determine susceptibility to cholesterol cholelithiasis in inbred mice: integrated activities of hepatic lipid regulatory enzymes

Lammert

Wang

Paigen

et al. 1999

“…It has been proposed that the ability of certain species, strains, and individuals to increase the production of bile acids in response to augmented ingestion of cholesterol is a major predictor of their susceptibility to diet-induced hypercholesterolemia (78). Rats and mice, which are generally noted as being resistant to diet-induced hypercholesterolemia, display increased expression of CYP7A1 and the production of bile acids in response to cholesterol-rich diets (58,(79)(80)(81)(82)(83)(84)(85)(86). The induction of CYP7A1 and bile acid synthesis by dietary cholesterol has also been observed in dogs (87) and in a hypercholesterolemia-resistant strain of rabbits (88).…”

Section: Induction Of Cyp7a1 and Bile Acid Synthesis By Dietary Cholesterolmentioning

confidence: 99%

“…One important consideration in evaluating individual responses to dietary cholesterol is the relative amount that is administered. In general, cholesterol feeding studies in rodents consist of feeding a diet containing ‫ف‬ 2% cholesterol (58,86), which represents a ‫ف‬ 100-fold increase compared with normal rodent diets. In contrast, humans are usually given much smaller increments in dietary cholesterol ( ‫ف‬ 3-fold increases over normal intake) (98).…”

Section: Induction Of Cyp7a1 and Bile Acid Synthesis By Dietary Cholesterolmentioning

confidence: 99%

Regulation of cholesterol-7α-hydroxylase: BAREly missing a SHP

Davis

Miyake

Hui

et al. 2002

155

Cholesterol-7 ␣ -hydroxylase (CYP7A1) regulates the pathway through which cholesterol is converted into bile acids. The unique detergent properties of bile acids are essential for the digestion and intestinal absorption of hydrophobic nutrients. Bile acids have potent toxic properties (e.g., membrane disruption) and there are a plethora of mechanisms to limit their accumulation in blood and tissues. The discovery of farnesoid X receptor (FXR), the nuclear receptor activated specifically by bile acids, has opened new insights into these mechanisms. Bile acid activation of FXR has been shown to repress the expression of CYP7A1 via increasing the expression of small heterodimer partner (SHP), a non-DNA binding protein. The increased abundance of SHP causes it to associate with liver receptor homolog (LRH)-1, an obligate factor required for transcription of CYP7A1. Recent studies show there is an "FXR/ SHP-independent" mechanism that also represses CYP7A1 expression. This "FXR/SHP-independent" pathway involves the interaction of bile acids with liver macrophages (i.e., Kupffer cells), which induces the expression, and secretion of cytokines. These inflammatory cytokines, which include tumor necrosis factor ␣ and interleukin-1 ␤ , act upon liver parenchymal cells causing a rapid repression of the CYP7A1 gene. -

“…5 and 7). Thus, although some strains of mice (e.g., BALB/c, C57BL/6, C3H/HeJ) differ in their expression and regulation of cholesterol 7␣-hydroxylase (27,28), we have been unable to find an obvious link between cholesterol catabolism and accumulation in the livers of C57BL/6, DBA/2, AKR, SJL, and 129 animals. The gene encoding the ileal lipid binding protein (29), which has been identified as a positional candidate for the regulation of hepatic cholesterol accumulation in QTL analyses using inbred rats (30), also is not contained within the chromosomal regions identified here.…”

Section: Discussionmentioning

confidence: 65%

Genetic analysis of cholesterol accumulation in inbred mice

Schwarz¹,

Davis

Vick³

et al. 2001

Genetic linkage analysis in the laboratory mouse identified chromosomal regions containing genes that contribute to cholesterol accumulation in the liver and plasma. Comparisons between five inbred strains of mice obtained from the Jackson Laboratory (DBA/2, AKR, C57BL/6, SJL, and 129P3) revealed a direct correlation between intestinal cholesterol absorption and susceptibility to diet-induced hypercholesterolemia. This correlation was lost in the F 1 generation arising from crosses between high-and lowabsorbing strains. Linkage analyses in AKxD recombinant inbred strains and 129xSJL129F 1 N 2 backcross mice identified four quantitative trait loci (QTL) that influenced L iver cho lesterol accumulation ( Lcho1-4 ) and one locus that affected P lasma cho lesterol accumulation ( Pcho1 ). These loci map to five chromosomes and, with one exception, are different from the seven QTL identified previously that influence intestinal cholesterol absorption. We conclude that a large number of genes affects the amount of cholesterol absorbed in the small intestine and its accumulation in the liver and plasma of inbred mice.