Hepatology in Space: Effects of Spaceflight and Simulated Microgravity on the Liver

Mathieu Vinken

Liver International. 2022;42(12):2599-2606.

Abstract and Introduction

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.

Introduction

Spaceflight considerably affects a number of physiological processes in astronauts. This does not come as a surprise considering the harsh environmental conditions in space. Most of these conditions are hardly, if at all, compatible with life on Earth, including radiation and microgravity. Microgravity in particular is gaining increasing attention, as weightlessness not only leads to the deterioration of bone and muscle, but also modifies body fluid distribution, the immuno-haematological system, cardiovascular functioning and the neurovestibular system.^[1,2] Effects of microgravity on metabolically highly active organs have been poorly documented thus far. Among those is the liver, which is a major hub for carbohydrate metabolism, lipid metabolism and xenobiotic biotransformation in the human body. Research in this direction is still in its infancy, yet is expected to boom in the upcoming years given the advent of touristic space travel and long-term missions to Mars. The present paper gives a state-of-the-art overview of the reported effects of microgravity on the liver, as experienced during real-life spaceflight as well as experimentally simulated on Earth in laboratory settings.

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Table 1. Effects of spaceflight and simulated microgravity on hepatic homeostasis in experimental animals
Species and sex	Test condition	Observation	Reference
Spaceflight
Male rats	9 days spaceflight	- Heat shock protein 90 ↓ - p53 ↓	¹⁴
Female mice	12 days spaceflight	Apoptosis ↑	¹⁸
Female mice	13.5 days spaceflight	- Oxidative stress ↑ - Autophagy ↑ - Mitochondrial impairment ↑	³¹
Male rats	14 days spaceflight	ALT^a ↑	⁸
Male rats	14 days spaceflight	- ALT^a ↑ - AST^a ↑	⁹
Male rats	18.5 days spaceflight	- ALT^a ↑ - AST^a ↑	⁷
Male mice	30 days spaceflight	- Oxidative stress ↑ - Sulfur anti-oxidants ↓ - Glutathione reducibility ↓	¹⁷
Simulated microgravity
Male rats	4 days of tail suspension	Heat shock protein 70 ↑	¹³
Male rats	7 days of tail suspension	Hepcidin ↑	¹⁶
Male mice	4 weeks of tail suspension	- ALT^a ↑ - AST^a ↑ - Inflammation ↑	¹⁰
Female mice	4 weeks of tail suspension	Inflammation ↑	¹⁵
Male rats	6 weeks of tail suspension	- ALT^a ↑ - AST^a ↑ - Proliferation ↓ - Alkaline phosphatase^a ↓	¹¹
Male rats	2 months of tail suspension	- ALT^a ↑ - AST^a ↑ - Apoptosis ↑ - Inflammation ↑ - Degeneration ↑ - Fibrosis ↑	¹²

Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase.
^aPlasma level.

Table 2. Effects of spaceflight and simulated microgravity on hepatic carbohydrate metabolism in experimental animals
Species and sex	Test condition	Observation	Reference
Spaceflight
Male rats	14 days of spaceflight	Glucose^a ↑	⁸
Male rats	14 days of spaceflight	Glycogen content ↑	⁹
Male rats	18.5 days of spaceflight	- Glycogen content ↑ - Gluconeogenesis ↑ - Glycogenolysis ↓	^24,26
Male rats	20 days of spaceflight	Glucose^a ↑	²²
Simulated microgravity
Male rats	10 days of suspension harness	- Gluconeogenesis ↑ - Glycogen content ↓	²⁸
Male rats	2 months of tail suspension	- Glucose^a ↓ - Glycogen content ↓	¹²
Female mice	4 weeks of tail suspension	- Glucose^a ↑ - Glycogen content ↑ - Gluconeogenesis ↑ - Glycolysis ↓	¹⁵

^aPlasma level.

Table 3. Effects of spaceflight and simulated microgravity on hepatic lipid metabolism in experimental animals
Species and sex	Test condition	Observation	Reference
Spaceflight
Female mice	13 days of spaceflight	- Steatosis ↑ - Retinol content ↓	³⁰
Female mice	13.5 days of spaceflight	Steatosis ↑	³¹
Male rats	14 days of spaceflight	- Fatty acid metabolism ↑ - Phospholipid content ↓	⁹
Male rats	18.5 days of spaceflight	- Palmitoleate ↑ - Fat mobilization ↑	^24,26
Male and female mice	13, 21, 37 or 42 days of spaceflight	- Lipid and fatty acid metabolism ↑ - Lipid and fatty acid processing ↑ - Lipid catabolism and mobilization ↑	³²
Simulated microgravity
Male rats	10 days of suspension harness	Steatosis ↑	²⁸
Male mice	4 weeks of tail suspension	Steatosis ↑	¹⁰

Table 4. Effects of spaceflight and simulated microgravity on hepatic biotransformation in experimental animals (CYP, cytochrome P450; GST, glutathione S-transferase)
Species and sex	Test condition	Observation	Reference
Spaceflight
Male rats	9 days of spaceflight	CYP4A1 ↑	¹⁴
Female mice	12 days of spaceflight	CYP4A1 ↑	¹⁸
Male rats	14 days of spaceflight	- CYP ↓ - GST ↓	⁹
Male rats	14 days of spaceflight	CYP ↓	³⁵
Male mice	30 days of spaceflight	- CYP1A2 ↑ - CYP2C29 ↑ - CYP2E1 ↑	³⁷
Simulated microgravity
Male rats	14 days of tail suspension	- CYP1A2 ↑ - CYP2C11 ↑ - CYP2D11 ↑ - CYP2E1 ↑ - CYP3A2 ↑	³⁸
Male rats	3 weeks of tail suspension	- CYP2C11 ↓ - CYP2E1 ↓	³⁹
Male mice	4 weeks of tail suspension	CYP3A ↓	¹⁰