Langner C A, Birkenmeier E H, Ben-Zeev O, Schotz M C, Sweet H O, Davisson M T, Gordon J I
Department of Biochemistry, Washington University School of Medicine, St. Louis, Missouri 63110.
J Biol Chem. 1989 May 15;264(14):7994-8003.
An autosomal recessive mutation, termed fatty liver dystrophy (fld), can be identified in neonatal mice by their enlarged and fatty liver (Sweet, H. O., Birkenmeier, E. H., and Davisson, M. T. (1988) Mouse News Letter 81, 69). We have examined the underlying metabolic abnormalities in fld/fld mice from postnatal days 3-40. Serum and hepatic triglyceride levels were elevated 5-fold in suckling fld/fld mice compared to their +/? littermates but abruptly resolved at the suckling/weaning transition. Blot hybridization analysis of liver and intestinal RNAs revealed a liver-specific increase in apolipoprotein (apo) A-IV and C-II mRNA concentrations (100- and 6-fold, respectively) that was limited to the suckling and early weaning stages in fld/fld mice. Resolution of these differences during the weaning period could not be delayed by prolonging suckling to the 20th postnatal day nor could the mutant phenotype be elicited in young adult animals with a high fat diet. Lipoprotein lipase (LPL) activity was reduced 16-fold in the white adipose tissue of fld/fld mice until the onset of weaning. Heart activity was decreased less than 2-fold, but there were no deficits in brown adipose tissue or liver. Hepatic lipase (HL) mRNA levels and activity were significantly reduced in fld/fld livers and sera, respectively, during the suckling period. Mapping studies show the fld locus to be distinct from loci encoding LPL, HL, and apoA-IV, and those responsible for the combined lipase deficiencies in cld/cld and W/Wv mice. These data suggest that the fld mutation is associated with developmentally programmed tissue-specific defects in the neonatal expression of LPL and HL activities and provide evidence for a new regulatory locus which affects these lipase activities. This mutation could serve as a useful model for (i) analyzing the homeostatic mechanisms controlling lipid metabolism in newborn mice and (ii) understanding and treating certain inborn errors in human triglyceride metabolism.
一种常染色体隐性突变，称为脂肪肝营养不良（fld），可在新生小鼠中通过其肝脏肿大和脂肪化来识别（斯威特，H.O.，伯克迈尔，E.H.，和戴维森，M.T.（1988年）《小鼠通讯》81，69）。我们研究了出生后3至40天的fld/fld小鼠潜在的代谢异常情况。与它们的+/?同窝小鼠相比，哺乳期的fld/fld小鼠血清和肝脏甘油三酯水平升高了5倍，但在哺乳/断奶过渡期突然恢复正常。对肝脏和肠道RNA进行印迹杂交分析显示，载脂蛋白（apo）A-IV和C-II mRNA浓度在肝脏中有特异性增加（分别为100倍和6倍），且仅限于fld/fld小鼠的哺乳和早期断奶阶段。在断奶期延长哺乳至出生后第20天并不能延迟这些差异的消失，用高脂肪饮食也不能在年轻成年动物中引发突变表型。直到断奶开始，fld/fld小鼠白色脂肪组织中的脂蛋白脂肪酶（LPL）活性降低了16倍。心脏中的活性降低不到2倍，但棕色脂肪组织或肝脏中没有缺陷。在哺乳期，fld/fld小鼠的肝脏中肝脂肪酶（HL）mRNA水平和血清中HL活性分别显著降低。定位研究表明，fld基因座与编码LPL、HL和apoA-IV的基因座不同，也与导致cld/cld和W/Wv小鼠联合脂肪酶缺乏的基因座不同。这些数据表明，fld突变与新生儿期LPL和HL活性表达中发育程序化的组织特异性缺陷有关，并为影响这些脂肪酶活性的新调控基因座提供了证据。这种突变可作为一个有用的模型，用于（i）分析控制新生小鼠脂质代谢的稳态机制，以及（ii）理解和治疗人类甘油三酯代谢中的某些先天性疾病。
