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

We found an inverse relationship between Med-Diet and NAFLD prevalence. Among NAFLD patients, good adherence to Med-Diet was associated with lower insulin resistance. Our findings suggest that Med-Diet may be a beneficial nutritional approach in NAFLD patients.

NAFLD is a polygenic condition but the individual and cumulative contribution of identified genes remains to be established. To get additional insight into the genetic architecture of NAFLD, GWAS-identified GCKR, PPP1R3B, NCAN, LYPLAL1 and TM6SF2 genes were resequenced by next generation sequencing in a cohort of 218 NAFLD subjects and 227 controls, where PNPLA3 rs738409 and MBOAT7 rs641738 genotypes were also obtained. A total of 168 sequence variants were detected and 47 were annotated as functional. When all functional variants within each gene were considered, only those in TM6SF2 accumulate in NAFLD subjects compared to controls (P = 0.04). Among individual variants, rs1260326 in GCKR and rs641738 in MBOAT7 (recessive), rs58542926 in TM6SF2 and rs738409 in PNPLA3 (dominant) emerged as associated to NAFLD, with PNPLA3 rs738409 being the strongest predictor (OR 3.12, 95% CI, 1.8-5.5, P < 0.001). A 4-SNPs weighted genetic risk score value >0.28 was associated with a 3-fold increased risk of NAFLD. Interestingly, rs61756425 in PPP1R3B and rs641738 in MBOAT7 genes were predictors of NAFLD severity. Overall, TM6SF2, GCKR, PNPLA3 and MBOAT7 were confirmed to be associated with NAFLD and a score based on these genes was highly predictive of this condition. In addition, PPP1R3B and MBOAT7 might influence NAFLD severity.

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