Engineered FGF19ΔKLB protects against intrahepatic cholestatic liver injury in ANIT-induced and Mdr2-/- mice model.

BACKGROUND: The major safety concern of the clinical application of wild type FGF19 (FGF19WT) emerges given that its extended treatment causes hepatocellular carcinoma. Therefore, we previously generated a safer FGF19 variant - FGF19ΔKLB, which have same effects on glycemic control and bile acid production but much less mitogenic activity. However, it remains unclear as to whether FGF19ΔKLB ameliorates intrahepatic cholestasis. RESULTS: We found that, similar to that of FGF19WT, the chronic administration of FGF19ΔKLB protects mice from cholestatic liver injury in these two models. The therapeutic benefits of FGF19ΔKLB on cholestatic liver damage are attributable, according to the following mechanistic investigation, to the reduction of BA production, liver inflammation, and fibrosis. More importantly, FGF19ΔKLB did not induce any tumorigenesis effects during its prolonged treatment. CONCLUSIONS: Together, our findings raise hope that FGF19ΔKLB may represent a useful therapeutic strategy for the treatment of intrahepatic cholestasis.

Functional Attenuation of UCP1 as the Potential Mechanism for a Thickened Blubber Layer in Cetaceans.

Uncoupling protein 1 (UCP1) is an essential protein in the mitochondrial inner membrane that mediates nonshivering thermogenesis (NST) and plays an important role in thermoregulation and fat deposition. However, the relationship between the evolution of UCP1 and fat deposition in the blubber layer in cetaceans remains unclear. Here, frameshift mutations, premature termination, and relaxed selection pressure (ω = 0.9557, P < 0.05) were detected in UCP1 in cetaceans, suggesting that UCP1 was inactivated during cetacean evolution. By time estimation, it was found that the inactivation of UCP1 in cetaceans occurred between 53.1 and 50.2 Ma. However, combined with findings from immunohistochemical analysis of the blubber layer of the Yangtze finless porpoise and in vitro functional assays, a premature termination of cetacean UCP1 resulted in a reduction of UCP1-mediated NST capacity (about 50%) and lipolytic capacity (about 40%), both of which were beneficial to maintain blubber layer and body temperature without excessive fat consumption. This study provides new insights into the molecular mechanisms of the blubber thickening in cetaceans and highlights the importance of UCP1 attenuation in cetaceans for secondary aquatic adaptation.

Decay of TRPV3 as the genomic trace of epidermal structure changes in the land-to-sea transition of mammals.

The epidermis plays an indispensable barrier function in animals. Some species have evolved unique epidermal structures to adapt to different environments. Aquatic and semi-aquatic mammals (cetaceans, manatees, and hippopotamus) are good models to study the evolution of epidermal structures because of their exceptionally thickened stratum spinosum, the lack of stratum granulosum, and the parakeratotic stratum corneum. This study aimed to analyze an upstream regulatory gene transient receptor potential cation channel, subfamily V, member 3 (TRPV3) of epidermal differentiation so as to explore the association between TRPV3 evolution and epidermal changes in mammals. Inactivating mutations were detected in almost all the aquatic cetaceans and several terrestrial mammals. Relaxed selective pressure was examined in the cetacean lineages with inactivated TRPV3, which might contribute to its exceptionally thickened stratum spinosum as the significant thickening of stratum spinosum in TRPV3 knock-out mouse. However, functional TRPV3 may exist in several terrestrial mammals due to their strong purifying selection, although they have "inactivating mutations." Further, for intact sequences, relaxed selective constraints on the TRPV3 gene were also detected in aquatic cetaceans, manatees, and semi-aquatic hippopotamus. However, they had intact TRPV3, suggesting that the accumulation of inactivating mutations might have lagged behind the relaxed selective pressure. The results of this study revealed the decay of TRPV3 being the genomic trace of epidermal development in aquatic and semi-aquatic mammals. They provided insights into convergently evolutionary changes of epidermal structures during the transition from the terrestrial to the aquatic environment.

Divergence of Tbx4 hindlimb enhancer HLEA underlies the hindlimb loss during cetacean evolution.

The cetacean hindlimb skeleton massively decreased to only vestigial limb elements as cetaceans evolved from land to aquatic lifestyles; however, the molecular mechanism underlying this major morphological transition remains unclear. In this study, four deletions and specific substitutions were detected in cetacean hindlimb enhancer A (HLEA), an enhancer that can regulate Tbx4 expression in hindlimb tissues to control hindlimb development. Transcriptional activation of HLEA was significantly weaker in bottlenose dolphin than mice, and this was found to be closely associated with cetacean-specific deletions. Furthermore, deletions in cetacean HLEA might disrupt HOX and PITX1 binding sites, which are required for enhancer activation. The ancestral state of these deletions was investigated, and all four specific deletions were found to have occurred after the species diverged from their common ancestor, suggesting that the deletion occurred recently, during a secondary aquatic adaptation. Taking these findings together, we suggest that cetacean-specific sequence changes reduced the Tbx4 gene expression pattern, and consequently drove the gradual loss of hindlimb in cetaceans.

Comparative genomics reveals molecular mechanisms underlying health and reproduction in cryptorchid mammals.

BACKGROUND: Mammals have wide variations in testicular position, with scrotal testes in some species and ascrotal testes in others. Although cryptorchidism is hazardous to human health, some mammalian taxa are natural cryptorchids. However, the evolution of testicular position and the molecular mechanisms underlying the maintenance of health, including reproductive health, in ascrotal mammals are not clear. RESULTS: In the present study, comparative genomics and evolutionary analyses revealed that genes associated with the extracellular matrix and muscle, contributing to the development of the gubernaculum, were involved in the evolution of testicular position in mammals. Moreover, genes related to testicular position were significantly associated with spermatogenesis and sperm fertility. These genes showed rapid evolution and the signature of positive selection, with specific substitutions in ascrotal mammals. Genes associated with testicular position were significantly enriched in functions and pathways related to cancer, DNA repair, DNA replication, and autophagy. CONCLUSIONS: Our results revealed that alterations in gubernaculum development contributed to the evolution of testicular position in mammals and provided the first support for two hypotheses for variation in testicular position in mammals, the "cooling hypothesis", which proposes that the scrotum provides a cool environment for acutely heat-sensitive sperm and the "training hypothesis", which proposes that the scrotum develops the sperm by exposing them to an exterior environment. Further, we identified cancer resistance and DNA repair as potential protective mechanisms in natural cryptorchids. These findings provide general insights into cryptorchidism and have implications for health and infertility both in humans and domestic mammals.

Genomic insights into body size evolution in Carnivora support Peto's paradox.

BACKGROUND: The range of body sizes in Carnivora is unparalleled in any other mammalian order-the heaviest species is 130,000 times heavier than the lightest and the longest species is 50 times longer than the shortest. However, the molecular mechanisms underlying these huge differences in body size have not been explored. RESULTS: Herein, we performed a comparative genomics analysis of 20 carnivores to explore the evolutionary basis of the order's great variations in body size. Phylogenetic generalized least squares (PGLS) revealed that 337 genes were significantly related to both head body length and body mass; these genes were defined as body size associated genes (BSAGs). Fourteen positively-related BSAGs were found to be associated with obesity, and three of these were under rapid evolution in the extremely large carnivores, suggesting that these obesity-related BSAGs might have driven the body size expansion in carnivores. Interestingly, 100 BSAGs were statistically significantly enriched in cancer control in carnivores, and 15 of which were found to be under rapid evolution in extremely large carnivores. These results suggested that large carnivores might have evolved an effective mechanism to resist cancer, which could be regarded as molecular evidence to support Peto's paradox. For small carnivores, we identified 15 rapidly evolving genes and found six genes with fixed amino acid changes that were reported to reduce body size. CONCLUSIONS: This study brings new insights into the molecular mechanisms that drove the diversifying evolution of body size in carnivores, and provides new target genes for exploring the mysteries of body size evolution in mammals.