Background & Aims
Nonalcoholic fatty liver disease (NAFLD) is a consequence of defects
in diverse metabolic pathways that involve hepatic accumulation of
triglycerides. Features of these aberrations might determine whether NAFLD
progresses to nonalcoholic steatohepatitis (NASH). We investigated whether
the diverse defects observed in patients with NAFLD are due to different
NAFLD subtypes with specific serum metabolomic profiles, and whether these
can distinguish patients with NASH from patients with simple steatosis.
Methods
We collected liver and serum from methionine adenosyltransferase 1a
knockout (MAT1A-KO) mice, which have chronically low level of hepatic
S-adenosylmethionine (SAMe) and spontaneously develop steatohepatitis, as
well as C57Bl/6 mice (controls); the metabolomes of all samples were
determined. We also analyzed serum metabolomes of 535 patients with
biopsy-proven NAFLD (353 with simple steatosis and 182 with NASH) and
compared them with serum metabolomes of mice. MAT1A-KO mice were also given
SAMe (30 mg/kg/day for 8 weeks); liver samples were collected and analyzed
histologically for steatohepatitis.
Results
Livers of MAT1A-KO mice were characterized by high levels of
triglycerides, diglycerides, fatty acids, ceramides, and oxidized fatty
acids, as well as low levels of SAMe and downstream metabolites. There was a
correlation between liver and serum metabolomes. We identified a serum
metabolomic signature associated with MAT1A-KO mice that was also present in
49% of the patients; based on this signature, we identified 2 NAFLD
subtypes. We identified specific panels of markers that could distinguish
patients with NASH from patients with simple steatosis for each subtype of
NAFLD. Administration of SAMe reduced features of steatohepatitis in
MAT1A-KO mice.
Conclusions
In an analysis of serum metabolomes of patients with NAFLD and
MAT1A-KO mice with steatohepatitis, we identified 2 major subtypes of NAFLD
and markers that differentiate steatosis from NASH in each subtype. These
might be used to monitor disease progression and identify therapeutic
targets for patients.
e Mitochondria are the main engine that generates ATP through oxidative phosphorylation within the respiratory chain. Mitochondrial respiration is regulated according to the metabolic needs of cells and can be modulated in response to metabolic changes. Little is known about the mechanisms that regulate this process. Here, we identify MCJ/DnaJC15 as a distinct cochaperone that localizes at the mitochondrial inner membrane, where it interacts preferentially with complex I of the electron transfer chain. We show that MCJ impairs the formation of supercomplexes and functions as a negative regulator of the respiratory chain. The loss of MCJ leads to increased complex I activity, mitochondrial membrane potential, and ATP production. Although MCJ is dispensable for mitochondrial function under normal physiological conditions, MCJ deficiency affects the pathophysiology resulting from metabolic alterations. Thus, enhanced mitochondrial respiration in the absence of MCJ prevents the pathological accumulation of lipids in the liver in response to both fasting and a high-cholesterol diet. Impaired expression or loss of MCJ expression may therefore result in a "rapid" metabolism that mitigates the consequences of metabolic disorders.
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