Inbuilt Mechanisms for Overcoming Functional Problems Inherent in Hepatic Microlobular Structure

Abstract

The spherical anatomy of human and rat liver lobules implies that more central cells have less time to carry out their function than more peripherally located cells because blood flows past them more rapidly. This problem could be overcome if more centrilobular cells could operate at higher temperatures than periportal cells. This study presents evidence for such a temperature gradient. Firstly, we use mathematical modelling to demonstrate that temperature increases towards the centre of the lobule. Secondly, we examine the distribution of a heat-generating protein and of a heat-sensitive protein across the rat and human liver lobules. Double-antibody staining of healthy liver from rat and human was used for visual scoring and for automated histomorphometric quantitation of the localisation of uncoupling protein-2 (known to generate heat) and of the transient receptor potential-v4 protein (known as a highly temperature-sensitive membrane protein). Both these proteins were found to be located predominantly in the centrilobular region of liver lobules. These findings support the suggestion that temperature gradients across the liver lobule may have evolved as a solution to the problem of reduced contact time between blood and cells at the centre as compared to the periphery of mammalian liver lobules.

Interactions between uncoupling protein 2 gene polymorphisms, obesity and alcohol intake on liver function: a large meta-analysed population-based study

“…BMI was calculated as weight (kg)/height (m) 2 . The usage of alcohol was assessed by questionnaire (19).…”

“…Uncoupling protein 2 (UCP2) is a heat-generating mitochondrial inner-membrane carrier protein that is widely expressed in tissues including adipocytes (1) and liver micro-lobules (2). Although liver is the major site of UCP2 expression in the rodent foetus, the levels decline soon after birth (3).…”

“…Although liver is the major site of UCP2 expression in the rodent foetus, the levels decline soon after birth (3). However, under pathologic conditions such as during inflammation (4) or steatosis, it increases (5); UCP2 gene expression has also been shown to occur in the hepatocytes of both normal adult rodents and healthy human adults, in the central area of the lobules (2). The role of UCP2 in obesity and liver disease is substantiated by the evidence that UCP2 enhanced fat accumulation in the liver, increased insulin resistance (6) and stimulated protective peripheral and central neural mechanisms in acute ethanol intake (7).…”

Robert Cohen

“…Failing to measure these rises by inserting fragile micro-thermocouples, he created a mathematical model of heat transfer down the radius of the lobule, which did show small increases. 12 Realising that the calculated heat differences would be insufficient, Cohen hypothesised that uncoupling proteins (UCP), notably UCP2, which prevent removal of energy from the electron transfer chain, might provide the explanation. Through immunohistochemistry studies on liver sections, Cohen and Boucher showed that UCP2 was indeed more highly concentrated at the centre of liver lobules in rats and humans.…”

A 3D porous media liver lobule model: the importance of vascular septa and anisotropic permeability for homogeneous perfusion

“…Cohen et al [34] also stated that the velocity near the CV is higher, resulting in a region of hepatocytes near the CV that have a much higher flux of blood passing them, as compared with hepatocytes that are located nearer the periphery. The flow patterns in the longitudinal sections through the PTs shown in Fig.…”