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  • Introduction The size of the liver of terrestrial mammals


    Introduction The size of the liver of terrestrial mammals obeys the allometric scaling law for animals as small as the Etruscan shrew (~1.8 g) and as large as the African elephant (~6600 kg) [1]. Since scaling deals with “structural and functional consequences of changes in size or scale among otherwise similar animals” [2], we can expect more similarities than differences between rodent and human livers. We will address the following topics:
    Lobar architecture
    How important is the presence of a gallbladder? Bile salts are detergents that aid in the GW3965 of dietary lipids, but also serve as signaling molecules. The gallbladder concentrates and stores bile between meals [40], which seems a potential trait for natural selection. The presence or absence of a gallbladder across mammalian species, nevertheless, resembles a checkerboard (Table 3). Although the list is not exhaustive (for more data, see [41,42]), a few trends can be found. Firstly, primates and carnivores seem to be obligatorily outfitted with a gallbladder, possibly because of their relatively high-fat diets. On the other hand, herbivorous odd-toed ungulates have, with the exception of manatees, no gallbladder. However, no predictions are possible for the equally herbivorous even-toed ungulates and the omnivorous rodents. Perhaps the most interesting examples are mice and rats, because these species belong to the same subfamily (Murinae). The early development of the caudal foregut and its glands is very similar in mice and rats, except that the biliary bud is missing ab initio in the rat [43,44]. The murine biliary bud epithelium expresses the gallbladder master regulator Sox17, whereas no Sox17 expression is identifiable in the hepatobiliary primordia of the rat [44]. Since Sox17 is expressed in rat embryonic stem cells [45,46], the Sox17-regulatory region or an upstream regulatory factor must have mutated. These data suggest that just one mutation can cause absence of a gallbladder in species. Since environmental factors, frequency and choice of food intake, and the nature of the bile salts produced are very similar in these species [47,48], a random mutation and little selection pressure seem the best explanation. The Atlantic forest hocicudo appears a case in point: among chromosomally identified specimens of this small South-American species, individuals with and without gallbladder were present [49]. In aggregate, these observations suggest that the presence or absence of a gallbladder does not represent a modification of the Bauplan, but more likely the functional loss of one or at most a few genes. An obvious, more experimental extension of these observations is to ablate the gallbladder. In humans, cholecystectomy is frequently performed, because 10–15% of the adult western population has bile stones and 1–4% become symptomatic within a year, especially when middle aged [50]. Humans [51] and mice [[52], [53], [54]] do quite well after cholecystectomy. The intervention decreases the bile acid pool, but because secretion rates of bile acids and cholesterol, and the enterohepatic recirculation rate are increased, in particular during fasting, digestion and absorption remain relatively unaffected ([[53], [54], [55], [56]]; for a recent review, see [40]). In fact, the main risk factor of cholecystectomy is age [50]. Solitary absence of the gallbladder, which is a rare feature in humans [[57], [58], [59]], does not seem to increase the risk for bile duct-related problems [57]. These findings, therefore, underscore our argument that the presence of a gallbladder does not represent an advantage in natural selection. The similar response to cholecystectomy in humans and mice is, nevertheless, somewhat surprising since rodent bile is much more hydrophilic than human bile due to their capacity to synthesize muricholic acids. The presence of just one additional gene in rodents, Cyp2c70, is responsible for the capacity to synthesize muricholic acid [60]. The capacity of mice and rats to synthesize muricholic acid allows urinary excretion of large amounts of bile acids after bile-duct ligation [61,62] and long-term survival even in the complete absence of intrahepatic bile ducts [63,64].