👤 M A Ballou

Mendelian randomization studies suggest a causal effect of lipoprotein(a) (Lp(a)) on atherosclerotic cardiovascular disease. Noncardiovascular effects (eg, diabetes risk) are inadequately investigated. In this noninterventional phenome-wide association study designed to better understand the potential causal role of Lp(a), direct causal phenotypic effects of exposure to Lp(a) were estimated. Also, the association between LPA null allele rs41272114 with type 2 diabetes was assessed, and ancestry-specific Lp(a) thresholds were determined. In the UK Biobank (n = 425,677 adults, 55% female), we studied 1,456 phenotypes spanning 18 classes using 4 ancestry-specific polygenic risk scores and false discovery rate multiple testing correction. Network deconvolution Mendelian randomization was leveraged to separate direct from indirect (ie, associations via mediating variables) causal phenotypic effects and account for confounding, reverse causation, and bidirectionality. Lp(a) was significantly associated with 80 phenotypes across 7 classes. Higher Lp(a) exposure had significant direct causal effects, independent of low-density lipoprotein cholesterol, on coronary artery disease (OR: 1.36; 95% CI: 1.21-1.54) and glycated hemoglobin (HbA1c; β = 0.099; 95% CI: 0.051-0.15) only. Very low Lp(a) exposure was not associated with type 2 diabetes (OR: 0.92; 95% CI: 0.64-1.31) or HbA1c (β = -0.016; 95% CI: -0.062 to 0.030). Among European and African ancestries, 86 (77th percentile) and 93 (59th percentile) nmol/L optimally discriminated myocardial infarction risk, respectively. Increasing Lp(a) exposure had direct, independent causal effects on coronary artery disease and HbA1c only; very low Lp(a) exposure is suggested to not be causally associated with type 2 diabetes. The optimal European and African ancestry threshold to stratify cardiovascular risk is comparable, and below 125/105 nmol/L in current U.S./European medical professional society guidelines. Show less

A critical regulator of autophagy is the Class III PI3K Vps34 (also called PIK3C3). Although Vps34 is known to play an essential role in autophagy in yeast, its role in mammals remains elusive. To elucidate the physiological function of Vps34 and to determine its precise role in autophagy, we have generated Vps34(f/f) mice, in which expression of Cre recombinase results in a deletion of exon 4 of Vps34 and a frame shift causing a deletion of 755 of the 887 amino acids of Vps34. Acute ablation of Vps34 in MEFs upon adenoviral Cre infection results in a diminishment of localized generation of phosphatidylinositol 3-phosphate and blockade of both endocytic and autophagic degradation. Starvation-induced autophagosome formation is blocked in both Vps34-null MEFs and liver. Liver-specific Albumin-Cre;Vps34(f/f) mice developed hepatomegaly and hepatic steatosis, and impaired protein turnover. Ablation of Vps34 in the heart of muscle creatine kinase-Cre;Vps34(f/f) mice led to cardiomegaly and decreased contractility. In addition, while amino acid-stimulated mTOR activation was suppressed in the absence of Vps34, the steady-state level of mTOR signaling was not affected in Vps34-null MEFs, liver, or cardiomyocytes. Taken together, our results indicate that Vps34 plays an essential role in regulating functional autophagy and is indispensable for normal liver and heart function. Show less

Objectives were to determine adipose tissue mRNA expression of peroxisome proliferator-activated receptor (PPAR)γ co-regulators, target enzymes and transcription regulators, inflammation-related genes, and adipokines in response to dietary long-chain fatty acids (LCFA). From -21 through 10 d relative to parturition cows were fed no supplemental LCFA (control), saturated LCFA (SFAT; mainly 16:0 and 18:0), or fish oil (FO). Lipid was fed at 250 g/d prepartum or approximately 1.5 to 1.9% of the previous day's dry matter intake postpartum. Transcript profiling of 35 genes via quantitative PCR was conducted on biopsies (n=5 cows/diet) collected at -14 and 11 d from parturition. Despite lower dry matter intake with FO, pre- and postpartal blood nonesterified fatty acids, β-hydroxybutyrate, and liver triacylglycerol were unaffected by treatment but increased after calving regardless of diet. Prepartal expression of adipogenic/lipogenic transcription regulators [CEBPA, CEBPB, RXRA, KLF5, and MLXIPL (formerly ChREBP)] and co-regulators (CARM1, EP300, NCOA1, MED1, NCOR2, and NRIP1) was upregulated by FO and SFAT versus control, whereas most enzymes involved in lipogenesis/triacylglycerol synthesis (FASN, SCD, DGAT2, and LPIN1) had greater expression only with FO. Expression of most adipogenic/lipogenic genes decreased after parturition, but feeding SFAT led to sustained upregulation of CEBPA, CEBPB, RXRA, several PPAR-co-activators, and DGAT2 and SCD, suggesting maintenance of a pro-adipogenic/pro-lipogenic state with SFAT. The co-activator CREBBP was greater in cows fed lipid and did not decrease after parturition, suggesting ligand activation of PPARγ. The greater peripartal expression of NFKB1 and TBK1 due to dietary lipid was suggestive of a local inflammatory response. At amounts fed prepartum, both FO and SFAT were effective in upregulating the adipose tissue PPARγ-gene network. In contrast, only SFAT led to sustaining that response. Overall, the observed expression patterns are suggestive of an adipogenic regulatory mechanism particularly responsive to SFAT. Show less