Regulation of Lipoprotein Assembly, Secretion and Fatty Acid β-Oxidation by Krüppel-Like Transcription Factor, klf-3

• Published in: Journal of molecular biology 2013-08, Vol.425 (15), p.2641-2655
• Main Authors: Zhang, Jun, Hashmi, Sanya, Cheema, Fatima, Al-Nasser, Nafla, Bakheet, Razan, Parhar, Ranjit S., Al-Mohanna, Futwan, Gaugler, Randy, Hussain, M. Mahmood, Hashmi, Sarwar
• Format: Article
• Language: English
• Subjects: Animals; apolipoprotein B; beta oxidation; biochemical pathways; C. elegans; Caenorhabditis elegans; Caenorhabditis elegans - genetics; Caenorhabditis elegans - metabolism; Caenorhabditis elegans Proteins; Caenorhabditis elegans Proteins - genetics; Caenorhabditis elegans Proteins - metabolism; cholesterol; dietary fat; energy; fatty acid β-oxidation; fatty acids; Fatty Acids - metabolism; Gene Expression Regulation; genes; genetics; homeostasis; human diseases; humans; intestines; klf; Kruppel-Like Transcription Factors; Kruppel-Like Transcription Factors - genetics; Kruppel-Like Transcription Factors - metabolism; lipoprotein assembly and secretion; Lipoproteins; Lipoproteins - metabolism; liver; metabolism; Mutant Proteins; Mutant Proteins - genetics; Mutant Proteins - metabolism; mutants; mutation; Oxidation-Reduction; risk factors; secretion; transcription factors; Transcription Factors - genetics; Transcription Factors - metabolism; triacylglycerols; very low density lipoprotein; vitamin D
• ISSN: 0022-2836; 1089-8638
• DOI: 10.1016/j.jmb.2013.04.020

Lipid metabolism is coordinately regulated through signaling networks that integrate biochemical pathways of fat assimilation, mobilization and utilization. Excessive diversion of fat for storage is a key risk factor for many fat-related human diseases. Dietary lipids are absorbed from the intestines and transported to various organs and tissues to provide energy and maintain lipid homeostasis. In humans, disparity between triglycerides (TG) synthesis and removal, via mitochondrial β-oxidation and VLDL (very low density lipoprotein) secretion, causes excessive TG accumulation in the liver. The mutation in Caenorhabditis elegans KLF-3 leads to high TG accumulation in the worm's intestine. Our previous data suggested that klf-3 regulates lipid metabolism by promoting fatty acid β-oxidation. Depletion of cholesterol in the diet has no effect on fat deposition in klf-3 (ok1975) mutants. Addition of vitamin D in the diet, however, increases fat levels in klf-3 worms. This suggests that excess vitamin D may be lowering the rate of fatty acid β-oxidation, with the eventual increase in fat accumulation. We also demonstrate that mutation in klf-3 reduces expression of C. elegans dsc-4 and/or vit genes, the orthologs of mammalian microsomal triglyceride transfer protein and apolipoprotein B, respectively. Both microsomal triglyceride transfer protein and apolipoprotein B are essential for mammalian lipoprotein assembly and transport, and mutation in both dsc-4 (qm182) and vit-5 (ok3239) results in high fat accumulation in worm intestine. Genetic interactions between klf-3 and dsc-4, as well as vit-5 genes, suggest that klf-3 may have an important role in regulating lipid assembly and secretion. [Display omitted] •Mammals regulate lipid secretion and distribution to maintain normal levels of TG in adipocytes.•Mutation in klf-3 reduces the number of mitochondria probably leading to lower β-oxidation.•Vitamin D increases fat levels in klf-3 mutant by lowering the rate of β-oxidation.•klf-3 may have an important role in regulating lipid assembly and secretion.•We establish that klf-3 controls lipid storage, secretion and mitochondrial proliferation.