Hepatology in space: Effects of spaceflight and simulated microgravity on the liver

Abstract

Microgravity as experienced during spaceflight affects a number of physiological processes in various organs. However, effects on the liver have yet been poorly documented. Nevertheless, the liver is a metabolically highly active organ involved in carbohydrate metabolism, lipid metabolism and xenobiotic biotransformation. The present paper provides an overview of the effects of microgravity on the liver observed in experimental animals during actual spaceflight and upon simulation of microgravity on Earth. These include (i) induction of liver injury and inflammation associated with apoptosis and oxidative stress, (ii) changes in liver carbohydrate metabolism resulting in the onset of a diabetogenic phenotype, (iii) modifications in hepatic lipid metabolism leading to early non‐alcoholic fatty liver disease and (iv) alterations of the hepatic xenobiotic biotransformation machinery. Although most of these observations remain to be fully validated in humans, appropriate measures to counteract liver pathogenesis should be considered, especially in view of long‐term space missions.

Spaceflight alters host-gut microbiota interactions

“…The free fatty acid and glycolysis regulating PPARα was also downregulated, and liver glycogen phosphorylase ( Pygl ) and glycogen synthase kinase 3 beta ( Gsk3β ) were significantly upregulated after 56 days of spaceflight (Fig 6G). Taken together, the indicated decrease in glycogen synthesis and increase in glycogenolysis is characteristic of insulin resistance leading to the elevated fasting plasma glucose to pre-diabetic levels previously observed in crew of the Mars500 analogue mission and during spaceflight 139–141 . Interestingly, in light of spaceflight induced changes to gut microbiota, upregulation of Gsk3β is also known to be activated by microbial-associated molecular patterns 142 and promotes acute liver failure through inhibition of the PPARα pathway 143 .…”

A Hierarchical Mechanotransduction System: From Macro to Micro

“…[ 6 ] As a result, the astronauts may experience multi‐systemic physio‐pathological changes, [ 44 ] such as telomere elongation, neurovestibular deconditioning, [ 45 ] spinal and skeletal dysfunction, [ 46 ] reduced baroreceptor responses, [ 47 ] altered immune capacity, [ 44 ] cardiovascular dysfunction, [ 48 ] and dysregulated metabolism. [ 49 ] It is increasingly believed that multiscale mechanotransduction mechanisms contribute considerably to these microgravity‐related deviations, [ 6 , 44 , 50 , 51 ] albeit the underlying mechanisms remain largely unknown.…”

Potential Roles of YAP/TAZ Mechanotransduction in Spaceflight-Induced Liver Dysfunction

“…As a guard against drug-induced injury in the body, the liver has a significant impact on the pharmacokinetic and pharmacodynamic properties of medications that are taken during spaceflight [7,8]. In addition, microgravity exposure dysregulates liver functions, resulting in apoptosis and oxidative stress-associated liver injury and inflammation, compromised carbohydrate metabolism, alterations in hepatic xenobiotic biotransformation machinery, and lipids deposition [9]. Evidently, these dysfunctions are correlated with microgravity-induced alterations of parenchymal and non-parenchymal cells inside the liver.…”

“…While diversified results still existed, most outcomes presented improved hepatocyte functions, such as albumin production and drug metabolism. However, the underlying mechano-biological coupling mechanisms are still far from being elucidated [9,11,12].…”