Objective-Angiopoietin-like 3 (Angptl3) is a regulator of lipoprotein metabolism at least by inhibiting lipoprotein lipase activity. Loss-of-function mutations in ANGPTL3 cause familial combined hypolipidemia through an unknown mechanism. Approach and Results-We compared lipolytic activities, lipoprotein composition, and other lipid-related enzyme/lipid transfer proteins in carriers of the S17X loss-of-function mutation in ANGPTL3 and in age-and sex-matched noncarrier controls. Gel filtration analysis revealed a severely disturbed lipoprotein profile and a reduction in size and triglyceride content of very low density lipoprotein in homozygotes as compared with heterozygotes and noncarriers. S17X homozygotes had significantly higher lipoprotein lipase activity and mass in postheparin plasma, whereas heterozygotes showed no difference in these parameters when compared with noncarriers. No changes in hepatic lipase, endothelial lipase, paraoxonase 1, phospholipid transfer protein, and cholesterol ester transfer protein activities were associated with the S17X mutation. Plasma free fatty acid, insulin, glucose, and homeostatic model assessment of insulin resistance were significantly lower in homozygous subjects compared with heterozygotes and noncarriers subjects. Conclusions-These results indicate that, although partial Angptl3 deficiency did not affect the activities of lipolytic enzymes, the complete absence of Angptl3 results in an increased lipoprotein lipase activity and mass and low circulating free fatty acid levels. This latter effect is probably because of decreased mobilization of free fatty acid from fat stores in human adipose tissue and may result in reduced hepatic very low density lipoprotein synthesis and secretion via attenuated hepatic free fatty acid supply. Altogether, Angptl3 may affect insulin sensitivity and play a role in modulating both lipid and glucose metabolism. Key Words: ANGPTL3 protein, human ◼ ANGPTL4 protein, human ◼ endothelial lipase, human ◼ familial combined hypolipidemia ◼ fatty acids, nonesterified ◼ hepatic lipase, human ◼ lipoprotein lipase

Familial combined hypolipidemia segregates as a recessive trait so that apolipoprotein B- and apolipoprotein A-I-containing lipoproteins are comprehensively affected only by the total deficiency of Angptl3. Familial combined hypolipidemia does not perturb whole-body cholesterol homeostasis and is not associated with adverse clinical sequelae.

Familial hypobetalipoproteinemia includes a heterogeneous group of inherited disorders of lipid metabolism typically characterized by very low levels (below the 5th percentile of age-and sex-specifi c values) of plasma low density lipoprotein cholesterol (LDL-C) and/or apo B ( 1, 2 ). Beside the very rare recessive disorder abetalipoproteinemia (ABL, OMIM # 200100) caused by mutation in the gene coding for the microsomal triglyceride transfer protein ( MTP ), the best-characterized cases are those with Press, September 19, 2013 DOI 10.1194 Clinical characteristics and plasma lipids in subjects with familial combined hypolipidemia: a pooled analysis Abbreviations: ANGPTL3, angiopoietin-like 3; BMI, body mass index; FBG, fasting blood glucose; FHBL, familial hypobetalipoproteinemia; FHBL2, familial combined hypolipidemia; FLI, fatty liver index; ␥ -GT, ␥ -glutamyltranspeptidase; GFR, glomerular fi ltration rate; Lp(a), lipoprotein(a); TG, triglyceride . ); National Institutes of Health Grant K08-HL-114642 (to N.S.); Massachusetts General Hospital (MGH) Research Scholar Award and Howard Goodman Fellowship (to S.K.); Donovan Family Foundation Grant (to S.K.), National Institutes of Health Grant R01 HL-107816 (to S.K.); and Fondation Leducq Grant (to S.K.). Manuscript received 7 May 2013 and in revised form 17 September 2013. Published, JLR Papers in

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