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

Frank Lammert, David Q.H. Wang, Beverly Paigen, Martin C. Carey

Research output: Contribution to journalArticle

64 Citations (Scopus)

Abstract

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 7α- 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 27-hydroxylase, and acyl-CoA: cholesterol acyltranferase, but not for cholesterol 7α-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.

Original languageEnglish (US)
Pages (from-to)2080-2090
Number of pages11
JournalJournal of Lipid Research
Volume40
Issue number11
StatePublished - Nov 1 1999
Externally publishedYes

Fingerprint

Cholelithiasis
Genes
Cholesterol
Lipids
Liver
Enzymes
Hydroxymethylglutaryl CoA Reductases
Cholestanetriol 26-Monooxygenase
Gallstones
Bile Acids and Salts
Cholesterol 7-alpha-Hydroxylase
Alleles
Nutrition
Sterol O-Acyltransferase
Inbred AKR Mouse
Diet
Phenotype
Cholic Acid
Acyl Coenzyme A
Dairies

Keywords

  • Acyl-CoA:cholesterol acyltransferase
  • Choleslerol 7α-hydroxylase
  • Gallstones
  • Genetics
  • HMG-CoA reductase
  • Microscopy
  • Recombinant inbred mice
  • Sterol 27-hydroxylase

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology
  • Cell Biology

Cite this

Phenotypic characterization of Lith genes that determine susceptibility to cholesterol cholelithiasis in inbred mice : Integrated activities of hepatic lipid regulatory enzymes. / Lammert, Frank; Wang, David Q.H.; Paigen, Beverly; Carey, Martin C.

In: Journal of Lipid Research, Vol. 40, No. 11, 01.11.1999, p. 2080-2090.

Research output: Contribution to journalArticle

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abstract = "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 7α- 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 27-hydroxylase, and acyl-CoA: cholesterol acyltranferase, but not for cholesterol 7α-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.",
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