Valérie Lamantia

The apoB-to-PCSK9 ratio: A new index for metabolic risk in humans

BACKGROUND Proprotein convertase subtilisin/kexin type 9 (PCSK9) shuttles low-density lipoprotein (LDL) receptors for degradation, thus upregulates LDL plasma clearance. Although PCSK9 loss of function is cardioprotective, its role in metabolic risks remains unknown. Increased apoB-lipoproteins uptake into nonhepatic tissues such as white adipose tissue (WAT) induces their dysfunction, which may be favored by lower plasma PCSK9. We hypothesized that lower plasma PCSK9 relative to apoB, or higher apoB-to-PCSK9 ratio, is a better predictor of metabolic disturbances than PCSK9 alone in humans. METHODS Thirty-three men and 48 postmenopausal women (>27 kg/m(2), aged 45-74 years, normoglycemic) underwent in-depth assessment of glucose and fat metabolism using high-fat meals, WAT biopsies, intravenous glucose-tolerance tests, and hyperinsulinemia clamps. RESULTS Plasma apoB correlated positively with fasting and postprandial triglycerides and chylomicron clearance (R = 0.44-0.66) and glucose-stimulated insulin secretion (R = 0.24) and negatively with insulin sensitivity (R = -0.28) and gynoid WAT in situ lipoprotein lipase activity (ie, ex vivo WAT function, R(2) = 0.34). Neither PCSK9 nor LDL cholesterol associated with these risks. In regression analysis that adjusted for body mass index, lower plasma PCSK9 strengthened the association of apoB to WAT dysfunction and insulin resistance. Moreover, plasma apoB-to-PCSK9 ratio correlated positively with all these metabolic risks and further associated positively with android-to-gynoid fat ratio (R = 0.41) and negatively with gynoid fat mass (R = -0.23, all P ≤ .05). No significant sex differences existed in these associations. CONCLUSIONS Lower plasma PCSK9 relative to apoB associates with metabolic risks and WAT dysfunction in normoglycemic obese subjects. We hypothesize that the plasma apoB-to-PCSK9 ratio provides a better clinical index than PCSK9 alone for monitoring early metabolic disturbances that may be promoted by reduction in plasma PCSK9.

Nutritional management of hyperapoB.

Plasma apoB is a more accurate marker of the risk of CVD and type 2 diabetes (T2D) than LDL-cholesterol; however, nutritional reviews targeting apoB are scarce. Here we reviewed eighty-seven nutritional studies and present conclusions in order of strength of evidence. Plasma apoB was reduced in all studies that induced weight loss of 6-12 % using hypoenergetic diets (seven studies; 5440-7110 kJ/d; 1300-1700 kcal/d; 34-50 % carbohydrates; 27-39 % fat; 18-24 % protein). When macronutrients were compared in isoenergetic diets (eleven studies including eight randomised controlled trials (RCT); n 1189), the diets that reduced plasma apoB were composed of 26-51 % carbohydrates, 26-46 % fat, 11-32 % protein, 10-27 % MUFA, 5-14 % PUFA and 7-13 % SFA. Replacement of carbohydrate by MUFA, not SFA, decreased plasma apoB. Moreover, dietary enriching with n-3 fatty acids (FA) (from fish: 1·1-1·7 g/d or supplementation: 3·2-3·4 g/d EPA/DHA or 4 g/d EPA), psyllium (about 8-20 g/d), phytosterols (about 2-4 g/d) or nuts (30-75 g/d) also decreased plasma apoB, mostly in hyperlipidaemic subjects. While high intake of trans-FA (4·3-9·1 %) increased plasma apoB, it is unlikely that these amounts represent usual consumption. Inconsistent data existed on the effect of soya proteins (25-30 g/d), while the positive association of alcohol consumption with low plasma apoB was reported in cross-sectional studies only. Five isoenergetic studies using Mediterranean diets (including two RCT; 823 subjects) reported a decrease of plasma apoB, while weaker evidence existed for Dietary Approaches to Stop Hypertension (DASH), vegetarian, Nordic and Palaeolithic diets. We recommend using a Mediterranean dietary pattern, which also encompasses the dietary components reported to reduce plasma apoB, to target hyperapoB and reduce the risks of CVD and T2D.

WAT apoC-I secretion: role in delayed chylomicron clearance in vivo and ex vivo in WAT in obese subjects

Reduced white adipose tissue (WAT) LPL activity delays plasma clearance of TG-rich lipoproteins (TRLs). We reported the secretion of apoC-I, an LPL inhibitor, from WAT ex vivo in women. Therefore we hypothesized that WAT-secreted apoC-I associates with reduced WAT LPL activity and TRL clearance. WAT apoC-I secretion averaged 86.9 ± 31.4 pmol/g/4 h and 74.1 ± 36.6 pmol/g/4 h in 28 women and 11 men with BMI ≥27 kg/m2, respectively, with no sex differences. Following the ingestion of a 13C-triolein-labeled high-fat meal, subjects with high WAT apoC-I secretion (above median) had delayed postprandial plasma clearance of dietary TRLs, assessed from plasma 13C-triolein-labeled TGs and apoB48. They also had reduced hydrolysis and storage of synthetic 3H-triolein-labeled (3H)-TRLs in WAT ex vivo (i.e., in situ LPL activity). Adjusting for WAT in situ LPL activity eliminated group differences in chylomicron clearance; while adjusting for plasma apoC-I, 3H-NEFA uptake by WAT, or body composition did not. apoC-I inhibited in situ LPL activity in adipocytes in both a concentration- and time-dependent manner. There was no change in postprandial WAT apoC-I secretion. WAT apoC-I secretion may inhibit WAT LPL activity and promote delayed chylomicron clearance in overweight and obese subjects. We propose that reducing WAT apoC-I secretion ameliorates postprandial TRL clearance in humans.

New Insights In Intestinal Sar1B GTPase Regulation and Role in Cholesterol Homeostasis.

Sar1B GTPase is a key component of Coat protein complex II (COPII)‐coated vesicles that bud from the endoplasmic reticulum to export newly synthesized proteins. The aims of this study were to determine whether Sar1B responds to lipid regulation and to evaluate its role in cholesterol (CHOL) homeostasis. The influence of lipids on Sar1B protein expression was analyzed in Caco‐2/15 cells by Western blot. Our results showed that the presence of CHOL (200 μM) and oleic acid (0.5 mM), bound to albumin, increases Sar1B protein expression. Similarly, supplementation of the medium with micelles composed of taurocholate with monooleylglycerol or oleic acid also stimulated Sar1B expression, but the addition of CHOL (200 μM) to micelle content did not modify its regulation. On the other hand, overexpression of Sar1B impacted on CHOL transport and metabolism in view of the reduced cellular CHOL content along with elevated secretion when incubated with oleic acid‐containing micelles for 24 h, thereby disclosing induced CHOL transport. This was accompanied with higher secretion of free‐ and esterified‐CHOL within chylomicrons, which was not the case when oleic acid was replaced with monooleylglycerol or when albumin‐bound CHOL was given alone. The aforementioned cellular CHOL depletion was accompanied with a low phosphorylated/non phosphorylated HMG‐CoA reductase ratio, indicating elevated enzymatic activity. Combination of Sar1B overexpression with micelle incubation led to reduction in intestinal CHOL transporters (NPC1L1, SR‐BI) and metabolic regulators (PCSK9 and LDLR). The present work showed that Sar1B is regulated in a time‐ and concentration‐dependent manner by dietary lipids, suggesting an adaptation to alimentary lipid flux. Our data also suggest that Sar1B overexpression contributes to regulation of CHOL transport and metabolism by facilitating rapid uptake and transport of CHOL. J. Cell. Biochem. 116: 2270–2282, 2015.

Su1773 The Small GTPase Sar1b: Expression Profile in Different Organs and Regulation by Dietary Lipids in Animal and Cell Models

Non-Hispanic Whites and US Hisp. US Hisp had a greater correlation of genetic burden to shorter time to diagnosis of IBD compared to FBH (p=0.04); those in the highest quartile of genetic risk score developed IBD on average 6 to 8 years earlier than those with a lower genetic burden (p=0.05). Conversely, time from emigration to development of IBD in FBH did not correlate with genetic burden. A higher genetic risk score correlates with a younger age of diagnosis in both US Hisp and in Non-Hispanic Whites but not in FBH. Future studies should address which genetic loci most closely correlate with a younger age of diagnosis and perhaps more aggressive IBD. These data suggest that environmental rather than genetic factors may dictate age of presentation in immigrants. 1. Jostins L, Ripke S, Weersma RK, et al. Host Microbiome interactions have shaped the genetic architecture of IBD. Nature. 2012; 491 (7422): 1999-24. Table 1. Inflammatory Bowel Disease (IBD) Demographics in Hispanics and Non-Hispanic Whites