ReviewNASH: a mitochondrial disease
Introduction
Despite our tendency to overeat, excessive fat accumulation was prevented in the past, as any excess weight soon impaired the physical fitness required to gather food, and to either fight or escape predators or foes. However, for the first time in human history, a large fraction of the population in affluent countries can now concomitantly indulge in rich food and physical idleness. The imbalance between food intake and the limited amount of fuels that can be burnt by mitochondria in inactive persons causes obesity, whose prevalence is increasing in affluent countries [1].
Obesity can lead to insulin resistance and hepatic steatosis, which triggers apoptosis, necrosis, Mallory bodies, an inflammatory cell infiltrate, and fibrosis in some patients [2]. The association of steatosis with these other liver lesions is called steatohepatitis, and the term non-alcoholic steatohepatitis (NASH) mostly refers to the steatohepatitis associated with insulin resistance.
Although the successive events triggering NASH are not fully understood, it seems that fat accumulation in myocytes triggers insulin resistance in muscle, thus causing pancreatic β-cells to release large amounts of insulin. High insulin levels increase hepatic free fatty acid (FFA) synthesis in the liver to cause steatosis, which can trigger NASH in some patients.
The purpose of this review is to discuss the evidence, mechanisms and implications of mitochondrial dysfunction at the successive steps leading to NASH, as already partially reviewed elsewhere [3], [4], [5], [6], [7], [8]. Beforehand, however, it may be useful to briefly recall some salient features of mitochondria.
Section snippets
Mitochondria: bacterial remnants assisted and controlled by nuclear genes
Like their bacterial ancestors [9], mitochondria have two membranes. The circular outer membrane surrounds the inter-membrane space, while the folded inner membrane invaginates into cristae protruding into the mitochondrial matrix. Like bacteria, mitochondria have their own circular DNA located in the matrix [10]. Although most of the ancient bacterial genes have been lost or have migrated to nuclear DNA [11], the residual human mitochondrial DNA still encodes for 13 of the polypeptides of the
Rats with low oxidative capacity develop obesity and other features of the metabolic syndrome
Rats were selectively bred for either low or high treadmill-running capacity [21]. After selection over 11 generations, low-capacity runners and high capacity runners were obtained, which differed 3.4-fold in the distance they could run before exhaustion. The rapidly exhausted rats had lower muscular PGC-1 expression and lower expression of oxidative phosphorylation polypeptides than rats able to run for long distances. The metabolically handicapped rats developed high blood glucose, insulin,
Mitochondrial function is insufficient in the skeletal muscle of obese and/or (pre)diabetic subjects
There is strong evidence for insufficient mitochondrial function in the skeletal muscle of obese subjects, type 2 diabetic patients and their offspring. In obese women, visceral fat was negatively correlated with mitochondrial CPT-I and citrate synthase activities in skeletal muscle [22]. The skeletal muscle mitochondria of obese patients had lower CPT, citrate synthase, and cytochrome c oxidase activities than those of lean individuals, and these activities did not improve after weight loss
Insufficient mitochondrial function contributes to insulin resistance in muscle
Together with excessive food intake, insufficient mitochondrial function in the muscles of obese and/or (pre)diabetic patients may cause intramyocellular fat accumulation [26], which itself seems to play a major role in the resistance of myocytes to the intracellular signaling effects of the insulin receptor (Fig. 3) [35].
In lean persons, insulin acts on the insulin receptor of myocytes to trigger the tyrosine phosphorylation of insulin receptor substrate, which activates phosphatidyl inositol
Insulin resistance is initially compensated for by increased insulin secretion, but mitochondrial dysfunction in pancreatic β-cells may eventually blunt insulin secretion to trigger diabetes
Insulin resistance in myocytes and adipocytes tends to slightly increase blood glucose levels after meals, thus triggering a swift release of insulin by pancreatic β-cells. Mitochondria play a major role in this process (Fig. 4). Glucose equilibrates across the plasma membrane of pancreatic β-cells, and undergoes glycolysis to pyruvate in the cytosol (Fig. 4) [40]. Mitochondrial pyruvate dehydrogenase then transforms pyruvate into acetyl-CoA, which enters the mitochondrial tricarboxylic acid
High glucose and/or insulin levels induce hepatic lipogenesis to cause hepatic steatosis
Normally, insulin inhibits the hormone-sensitive lipase of adipocytes to block adipose tissue lipolysis [53]. In contrast, the fat-engorged, insulin-resistant adipocytes of obese persons keep releasing FFAs in the circulation despite high insulin levels (Fig. 5). The increased release of FFAs from adipose tissue increases plasma FFAs [54]. The high plasma FFA levels may either increase hepatic FFA uptake, or may at least maintain a normal rate of hepatic FFA uptake, despite increased hepatic
Hepatic mitochondrial dysfunction contributes to the genesis of NASH lesions
Patients with NASH have an impaired in vivo ability to re-synthesize ATP after a fructose challenge, which transiently depletes hepatic ATP [84]. Their hepatic mitochondria exhibit ultrastructural lesions, with the presence of para-cristalline inclusions in megamitochondria [72], [85]. Patients with NASH have decreased hepatic mitochondrial DNA levels [86], decreased protein expression of several mitochondrial DNA-encoded polypeptides [86], [87], and lower activity of complexes I, III, IV and V
Conclusions
We believe that NASH can be considered, to some extent, as a mitochondrial disease, since mitochondrial dysfunction is involved at all successive steps leading to NASH.
Firstly, lack of exercise (and possibly a PGC-1 or other genetic polymorphisms) may decrease mitochondrial biogenesis and fat oxidation in skeletal muscle, and this insufficient mitochondrial function could be further impaired during old age, as a consequence of the accumulation of somatic mitochondrial DNA mutations. Together
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