Novel metabolic phenotypes in lecithin cholesterol acyltyransferase-deficient mice.

Abstract

PURPOSE OF REVIEW:

Lecithin cholesterol acyltyransferase (LCAT) deficiency is a rare monogenic disorder causing lipoprotein dysregulation and multiple organ dysfunctions, including renal impairment. LCAT knockout mice have been shown informative in elucidating mechanisms of many major clinical morbid phenotypes. Extended characterization of the LDL receptor/LCAT double knockout (Ldlr/Lcat-DKO or DKO) mice had led to the discovery of a number of novel protective metabolic phenotypes, including resistance to obesity, nonalcoholic steatohepatitis (NASH) and insulin resistance. We seek to integrate the findings to explore novel pathogenic pathways.

RECENT FINDINGS:

The chow fed DKO mice were found more insulin sensitive than their Ldlr-KO controls. Joint analyses of the three strains (DKO, Ldlr-KO and wild-type) revealed differential metabolic responses to a high cholesterol diet (HCD) vs. high-fat diet (HFD). DKO mice are protected from HFD-induced obesity, hepatic endoplasmic reticulum (ER) stress, insulin resistance, ER cholesterol and NASH markers (steatosis and inflammasomes). Joint analysis revealed the HFD-induced NASH is dependent on de-novo hepatic cholesterol biosynthesis. DKO mice are protected from HCD-induced hepatic ER stress, ER cholesterol, but not NASH, the latter likely due to cholesterol crystal accumulation. DKO mice were found to develop ectopic brown adipose tissue (BAT) in skeletal muscle. Ectopic BAT derived in part from myoblast in utero and from adult satellite cells. Primed expression of PRDM16 and UCP in quiescent satellite cell caused by LCAT deficiency synergizes with cell cholesterol depletion to induce satellite cell-to-BAT transdifferentiation.

SUMMARY:

Metabolic phenotyping of selective LCAT null mice led to the discovery of novel metabolically protective pathways.

• Authors: Dominic S Ng
• Journal: Current opinion in lipidology (Curr Opin Lipidol) Vol. 29 Issue 2 Pg. 104-109 (04 2018) ISSN: 1473-6535 [Electronic] England
• PMID: 29369831 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Review)

Chemical References

• Dietary Fats
• Cholesterol
• Phosphatidylcholine-Sterol O-Acyltransferase

Topics

• Animals
• Cholesterol (metabolism)
• Dietary Fats (pharmacology)
• Gene Knockout Techniques
• Mice
• Phenotype
• Phosphatidylcholine-Sterol O-Acyltransferase (genetics, metabolism)