ApoB siRNA-induced Liver Steatosis is Resistant to Clearance by the Loss of Fatty Acid Transport Protein 5 (Fatp5)

The association between hypercholesterolemia and elevated serum apolipoprotein B (APOB) has generated interest in APOB as a therapeutic target for patients at risk of developing cardiovascular disease. In the clinic, mipomersen, an antisense oligonucleotide (ASO) APOB inhibitor, was associated with a trend toward increased hepatic triglycerides, and liver steatosis remains a concern. We found that siRNA-mediated knockdown of ApoB led to elevated hepatic triglycerides and liver steatosis in mice engineered to exhibit a human-like lipid profile. Many genes required for fatty acid synthesis were reduced, suggesting that the observed elevation in hepatic triglycerides is maintained by the cell through fatty acid uptake as opposed to fatty acid synthesis. Fatty acid transport protein 5 (Fatp5/Slc27a5) is required for long chain fatty acid (LCFA) uptake and bile acid reconjugation by the liver. Fatp5 knockout mice exhibited lower levels of hepatic triglycerides due to decreased fatty acid uptake, and shRNA-mediated knockdown of Fatp5 protected mice from diet-induced liver steatosis. Here, we evaluated if siRNA-mediated knockdown of Fatp5 was sufficient to alleviate ApoB knockdown-induced steatosis. We determined that, although Fatp5 siRNA treatment was sufficient to increase the proportion of unconjugated bile acids 100-fold, consistent with FATP5's role in bile acid reconjugation, Fatp5 knockdown failed to influence the degree, zonal distribution, or composition of the hepatic triglycerides that accumulated following ApoB siRNA treatment

Exploring the Link Between Genetic and Morpho-Anatomical Diversity in the Swordfish's Rostra

Aim The swordfish, Xiphias gladius (L. 1758), belongs to order Perciformes and represents the only living species of genus Xiphias. The anatomical characteristic that distinguishes adult individuals is the upper jaw, which develops enormously to form a rostrum, of a considerable size. Despite the fully preserved external morphology, Di Natale et al. (1996) defined for the first time different internal structures describe as “with canals”, characterized by bony bundles running longitudinally and separated by tissue striations of lower density and “with chambers”, characterized by multiple chambers ranging from a few to dozens of units located in the central area of the sword. The aim of the present study is to verify the existence of an association between different internal rostrum morphologies with the occurrence of two mitochondrial haplogroups in Mediterranean specimens, as reported by several studies (Smith et al. 2015; Righi et al. 2020). Methods Genetic characterization was based on mitochondrial markers such as the CR (control region), NADH dehydrogenase subunit 2 (ND2), and cytochrome oxidase subunit 1 (COI); while the swordfish internal structures were inspected using x-ray or CT analysis. Results The haplotype networks obtained from the three mitochondrial markers support the presence of two distinct evolutionary lineages of X. gladius in the Mediterranean Sea, confirming the results described by various authors (see above). However, no relationship was found between the two clades and rostra morphologies when phylogenetic and genetic differentiation analyses were applied. Main conclusion Further alternative methodologies are currently employed to investigate the potential correlation between the genetic and morpho-anatomical diversity of the swordfish's rostra. From a genetic standpoint, we will be applying cutting-edge next-generation sequencing techniques, specifically 2bRAD. The availability of X-rays or CT scans will allow us to investigate the morpho-anatomical details of the rostra internal structure with specific programs for geometric morphometrics