Abstract
Non-alcoholic fatty liver disease (NAFLD) is a major risk
factor leading to chronic liver disease and type 2
diabetes. Here we chart liver metabolic activity and
functionality in NAFLD by integrating global
transcriptomic data, from human liver biopsies, and
metabolic flux data, measured across the human splanchnic
vascular bed, within a genome-scale model of human
metabolism. We show that an increased amount of liver fat
induces mitochondrial metabolism, lipolysis,
glyceroneogenesis and a switch from lactate to glycerol
as substrate for gluconeogenesis, indicating an intricate
balance of exacerbated opposite metabolic processes in
glycemic regulation. These changes were associated with
reduced metabolic adaptability on a network level in the
sense that liver fat accumulation puts increasing demands
on the liver to adaptively regulate metabolic responses
to maintain basic liver functions. We propose that
failure to meet excessive metabolic challenges coupled
with reduced metabolic adaptability may lead to a vicious
pathogenic cycle leading to the co-morbidities of NAFLD.
Original language | English |
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Article number | 8994 |
Journal | Nature Communications |
Volume | 7 |
DOIs | |
Publication status | Published - 2016 |
MoE publication type | A1 Journal article-refereed |
Keywords
- Medical research
- Metabolism
- non-alcoholic fatty liver disease
- Transcriptomics