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Genetic variation in the FAM13A (Family with Sequence Similarity 13 Member A) locus has been associated with several glycemic and metabolic traits in genome-wide association studies (GWAS). Here, we demonstrate that in humans, FAM13A alleles are associated with increased FAM13A expression in subcutaneous adipose tissue (SAT) and an insulin resistance-related phenotype (e.g. higher waist-to-hip ratio and fasting insulin levels, but lower body fat). In human adipocyte models, knockdown of FAM13A in preadipocytes accelerates adipocyte differentiation. In mice, Fam13a knockout (KO) have a lower visceral to subcutaneous fat (VAT/SAT) ratio after high-fat diet challenge, in comparison to their wild-type counterparts. Subcutaneous adipocytes in KO mice show a size distribution shift toward an increased number of smaller adipocytes, along with an improved adipogenic potential. Our results indicate that GWAS-associated variants within the FAM13A locus alter adipose FAM13A expression, which in turn, regulates adipocyte differentiation and contribute to changes in body fat distribution., Genetic variants in the FAM13A locus have been associated with anthropometric and glycemic traits. Here, using fine-mapping, in vitro knockdown studies in pre-adipocytes and in vivo knockout in mice, the authors show that FAM13A is involved in regulating fat distribution and metabolic traits.

We recently identified human N-acetyltransferase 2 (NAT2) as an insulin resistance (IR) gene. Here we examine the cellular mechanism linking NAT2 to IR and find that Nat1 (mouse ortholog of NAT2) is co-regulated with key regulators of mitochondria. RNA-interference mediated silencing of Nat1 led to mitochondrial dysfunction characterized by increased intracellular reactive oxygen species and mitochondrial fragmentation as well as decreased mitochondrial membrane potential, biogenesis, mass, cellular respiration and ATP generation. These effects were consistent in 3T3-L1 adipocytes, C2C12 myoblasts and in tissues from Nat1 deficient mice including white adipose tissue, heart and skeletal muscle. Nat1 deficient mice had changes in plasma metabolites and lipids consistent with a decreased ability to utilize fats for energy and a decrease in basal metabolic rate and exercise capacity without altered thermogenesis. Collectively, our results suggest that Nat1 deficiency results in mitochondrial dysfunction, which may constitute a mechanistic link between this gene and IR.

Lipoprotein(a) [Lp(a)] consists of a low-density lipoprotein (LDL)-like core and apo(a), a large molecular weight glycoprotein. Apo(a) is highly homologous to plas‐ minogen, yet in contrast exhibits a unique size polymorphism that is characterized by an increasing number of kringle-IV (K-IV) repeats. The number of K-IV repeats ranges from n = 2 to n = 40 or even higher. Apo(a) is synthesized almost exclusively in the liver and there is still some debate whether the assembly of Lp(a) from LDL and apo(a) occurs inside the liver cells or in the circulating blood. The plasma Lp(a) con‐ centration is markedly skewed reaching from 200 mg/dl. The plasma concentration is >90% genetically determined and correlates negatively with the num‐ ber of K-IV repeats. In the apo(a) promoter, there are numerous response elements for transcription factors and nuclear receptors that regulate apo(a) expression. The HNF4α binding sequence appears to be the most important one in that respect, yet further work needs to be done to unravel the key features of apo(a) biosynthesis un‐ der different conditions. Importantly, activation of FXR causes the dissociation of HNF4α α from its response element and in turn a significant downregulation of apo(a) transcription. Undoubtedly, Lp(a) is one of the most atherogenic lipoproteins and recent large epi‐ demiological studies document quite impressively that Lp(a) is an independent causal risk factor for coronary heart disease (CHD) and myocardial infarction. This fact led to the development of specific medications to reduce Lp(a) in patients with high plas‐ ma concentrations. Among the registered lipid-lowering drugs, only nicotinic acid has a consistently significant Lp(a)-lowering effect, and we recently succeeded in elucidat‐ ing the mode of action of this drug. There are numerous medications in the pipeline for the treatment of hyper-Lp(a). Among those that are currently in clinical trials, CETP inhibitors, PCSK9 antibodies, MTP inhibitors as well as antisense oligonucleoti‐ des (ASO), such as the specific APO(a)Rx® from ISIS, which is directed against apo(a)mRNA and appears to be the most promising drug as it lowers Lp(a) levels by more than 90%. Lp(a) emerged as an important screening parameter to assess coronary atherosclerosis risk. Its quantitation in the clinical laboratory was, for a long time, quite problematic © 2015 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. since commonly accepted reference materials and standardized analytical methods were lacking. However, newer commercial assays based on nephelometry or tur‐ bidimetry, or ELISA using monoclonal antibodies that recognize single epitopes in apo(a), warrant comparable interlaboratory results.

Elevated plasma lipoprotein(a) (LPA) levels are recognized as an independent risk factor for cardiovascular diseases. Our knowledge on LPA metabolism is incomplete, which makes it difficult to develop LPA-lowering medications. Nicotinic acid (NA) is the main drug recommended for the treatment of patients with increased plasma LPA concentrations. The mechanism of NA in lowering LPA is virtually unknown. To study this mechanism, we treated transgenic (tg) APOA mice with NA and measured plasma APOA and hepatic mRNA levels. In addition, mouse and human primary hepatocytes were incubated with NA, and the expression of APOA was followed. Feeding 1% NA reduced plasma APOA and hepatic expression of APOA in tg-APOA mice. Experiments with cultured human and mouse primary hepatocytes in addition to reporter assays performed in HepG2 cells revealed that NA suppresses APOA transcription. The region between −1446 and −857 of the human APOA promoter harboring several cAMP response element binding sites conferred the negative effect of NA. In accordance, cAMP stimulated APOA transcription, and NA reduced hepatic cAMP levels. It is suggested that cAMP signaling might be involved in reducing APOA transcription, which leads to the lowering of plasma LPA.