In non-alcoholic fatty liver disease (NAFLD), lipid build-up and the resulting damage is known to occur more severely in pericentral cells. Due to the complexity of studying individual regions of the sinusoid, the causes of this zone specificity and its implications on treatment are largely ignored. In this study, a computational model of liver glucose and lipid metabolism is presented which treats the sinusoid as the repeating unit of the liver rather than the single hepatocyte. This allows for inclusion of zonated enzyme expression by splitting the sinusoid into periportal to pericentral compartments. By simulating insulin resistance (IR) and high intake diets leading to the development of steatosis in the model, we identify key differences between periportal and pericentral cells accounting for higher susceptibility to pericentral steatosis. Secondly, variation between individuals is seen in both susceptibility to steatosis and in its development across the sinusoid. Around 25% of obese individuals do not show excess liver fat, whilst 16% of lean individuals develop NAFLD. Furthermore, whilst pericentral cells tend to show higher lipid levels, variation is seen in the predominant location of steatosis from pericentral to pan-sinusoidal or azonal. Sensitivity analysis was used to identify the processes which have the largest effect on both total hepatic triglyceride levels and on the sinusoidal location of steatosis. As is seen in vivo, steatosis occurs when simulating IR in the model, predominantly due to increased uptake, along with an increase in de novo lipogenesis. Additionally, concentrations of glucose intermediates including glycerol-3-phosphate increased when simulating IR due to inhibited glycogen synthesis. Several differences between zones contributed to a higher susceptibility to steatosis in pericentral cells in the model simulations. Firstly, the periportal zonation of both glycogen synthase and the oxidative phosphorylation enzymes meant that the build-up of glucose intermediates was less severe in the periportal hepatocyte compartments. Secondly, the periportal zonation of the enzymes mediating β-oxidation and oxidative phosphorylation resulted in excess fats being metabolised more rapidly in the periportal hepatocyte compartments. Finally, the pericentral expression of de novo lipogenesis contributed to pericentral steatosis when additionally simulating the increase in sterol-regulatory element binding protein 1c (SREBP-1c) seen in NAFLD patients in vivo. The hepatic triglyceride concentration was predicted to be most sensitive to inter-individual variation in the activity of enzymes which, either directly or indirectly, determine the rate of free fatty acid (FFA) oxidation. The concentration was most strongly dependent on the rate constants for β-oxidation and oxidative phosphorylation. It also showed moderate sensitivity to the rate constants for processes which alter the allosteric inhibition of β-oxidation by acetyl-CoA. The predominant sinusoidal location of steatosis meanwhile was most s...

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The ArgumentMany of the epistemological issues that occupied natural philosophers of the seventeenth century were expressed visually in title-page engravings. One of those issues concerned the relative status to be accorded to evidence of the senses, as compared to knowledge gained by faith or reason. In title-page illustrations, the various arguments were often waged by a series of light metaphors: the Light of Reason, the Light of Nature, and the Lights of Sense, Scripture, and Grace. When such illustrations are examined with the authors' theological views in mind, it becomes apparent that in the first half of the seventeenth century, Catholic authors favored the Light of Reason as a source of truth, while Protestant authors favored the Light of Nature. Since by the end of the century it was widely accepted by scientists of all religious persuasions that certain knowledge must be grounded in sense evidence and the direct study of nature, one might argue that in this instance Protestantism was responsible for nurturing an important development of the Scientific Revolution. However, the skewed nature of the sample (the Catholics who used light metaphors were mostly Jesuits; the Protestants who did so mostly alchemists) and the large number of counterexamples available (many Catholic scientists believed in the ascendancy of the senses but failed to engage in metaphorical warfare) mitigate against taking this offshoot of the Merton thesis too seriously.

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