Altered metabolism of low-density lipoprotein and very-low-density lipoprotein remnant in autosomal recessive hypercholesterolemia: results from stable isotope kinetic study in vivo.

Abstract

BACKGROUND:

Autosomal recessive hypercholesterolemia (ARH) exhibits different responsiveness to statins compared with that in homozygous familial hypercholesterolemia (FH). However, few data exist regarding lipoprotein metabolism of ARH. Therefore, we aimed to clarify lipoprotein metabolism, especially the remnant lipoprotein fractions of ARH before and after statin therapy.

METHODS AND RESULTS:

We performed a lipoprotein kinetic study in an ARH patient and 7 normal control subjects, using stable isotope methodology (10 mg/kg of [(2)H(3)]-leucine). These studies were performed at baseline and after the 20 mg daily dose of atorvastatin. Tracer/tracee ratio of apolipoprotein B (apoB) was determined by gas chromatography/mass spectrometry and fractional catabolic rates (FCR) were determined by multicompartmental modeling, including remnant lipoprotein fractions. FCR of low-density lipoprotein (LDL) apoB of ARH was significantly lower than those of control subjects (0.109 versus 0.450±0.122 1/day). In contrast, the direct removal of very-low-density lipoprotein remnant was significantly greater in ARH than those in control subjects (47.5 versus 2±2%). Interestingly, FCR of LDL apoB in ARH dramatically increased to 0.464 1/day, accompanying reduction of LDL cholesterol levels from 8.63 to 4.22 mmol/L after treatment with atorvastatin of 20 mg/d for 3 months.

CONCLUSIONS:

These results demonstrate that ARH exhibits decreased LDL clearance associated with decreased FCR of LDL apoB and increased clearance for very-low-density lipoprotein remnant. We suggest that increased clearance of remnant lipoprotein fractions could contribute to the great responsiveness to statins, providing new insights into the lipoprotein metabolism of ARH and the novel pharmacological target for LDLRAP1.

• Authors: Hayato Tada, Masa-aki Kawashiri, Katsunori Ikewaki, Yoshio Terao, Tohru Noguchi, Chiaki Nakanishi, Masayuki Tsuchida, Mutsuko Takata, Kenji Miwa, Tetsuo Konno, Kenshi Hayashi, Atsushi Nohara, Akihiro Inazu, Junji Kobayashi, Hiroshi Mabuchi, Masakazu Yamagishi
• Journal: Circulation. Cardiovascular genetics (Circ Cardiovasc Genet) Vol. 5 Issue 1 Pg. 35-41 (Feb 01 2012) ISSN: 1942-3268 [Electronic] United States
• PMID: 22157599 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anticholesteremic Agents
• Apolipoproteins B
• Heptanoic Acids
• Lipoproteins, LDL
• Lipoproteins, VLDL
• Pyrroles
• Atorvastatin

Topics

• Adult
• Aged
• Anticholesteremic Agents (therapeutic use)
• Apolipoproteins B (metabolism)
• Atorvastatin
• Gas Chromatography-Mass Spectrometry
• Heptanoic Acids (therapeutic use)
• Humans
• Hypercholesterolemia (diagnosis, drug therapy, metabolism, pathology)
• Isotope Labeling
• Kinetics
• Lipoproteins, LDL (metabolism)
• Lipoproteins, VLDL (metabolism)
• Male
• Middle Aged
• Pedigree
• Pyrroles (therapeutic use)