Research Article Details
| Article ID: | A31996 |
| PMID: | 29369831 |
| Source: | Curr Opin Lipidol |
| Title: | 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. |
| DOI: | 10.1097/MOL.0000000000000486 |
| Strategy ID | Therapy Strategy | Synonyms | Therapy Targets | Therapy Drugs | |
|---|---|---|---|---|---|
| S01 | Improve insulin resistance | insulin sensitizer; insulin resistance; glucose tolerance | Biguanide: increases 5-AMP activated protein kinase signaling; SGLT-2 inhibitor; Thiazalidinedione: selective PPAR-γ agonists; GLP-1 agonist | Metformin; Empagliflozin; Canagliflozin; Rosiglitazone; Pioglitazone; Liraglutide | Details |
| Diseases ID | DO ID | Disease Name | Definition | Class | |
|---|---|---|---|---|---|
| I05 | 9352 | Type 2 diabetes mellitus | A diabetes that is characterized by chronic hyperglycaemia with disturbances of carbohydrate, fat and protein metabolism resulting from defects in insulin secretion, insulin action, or both. A diabetes mellitus that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. http://en.wikipedia.org/wiki/Diabetes, http://en.wikipedia.org/wiki/Diabetes_mellitus_type_2 | disease of metabolism/inherited metabolic disorder/ carbohydrate metabolic disorder/glucose metabolism disease/diabetes/ diabetes mellitus | Details |
| I14 | 9970 | Obesity | An overnutrition that is characterized by excess body fat, traditionally defined as an elevated ratio of weight to height (specifically 30 kilograms per meter squared), has_material_basis_in a multifactorial etiology related to excess nutrition intake, decreased caloric utilization, and genetic susceptibility, and possibly medications and certain disorders of metabolism, endocrine function, and mental illness. https://en.wikipedia.org/wiki/Obesity | disease of metabolism/acquired metabolic disease/ nutrition disease/overnutrition | Details |
| Drug ID | Drug Name | Type | DrugBank ID | Targets | Category | Latest Progress | |
|---|---|---|---|---|---|---|---|
| D080 | Citrulline | Chemical drug | DB00155 | -- | -- | Under clinical trials | Details |
| D273 | Phosphatidylcholine | Chemical drug | DB15834 | -- | -- | Under clinical trials | Details |
| D075 | Choline | Supplement | DB00122 | PLD2 product of; PLD1 product of | -- | Under clinical trials | Details |
| D182 | Insulin | Biological drug | DB00030 | INSR agonist; CPE modulator&product of | -- | Under clinical trials | Details |