1. NASH: a mitochondrial disease
Dominique Pessayre, Bernard Fromenty 
Journal of Hepatology 
Volume 42, Issue 6, Pages (June 2005)
DOI: /j.jhep
Copyright © 2005 European Association for the Study of the Liver Terms and Conditions

2. Fig. 1
Oxidative metabolism and energy production by mitochondria. The oxidation of pyruvate and FFA in mitochondria produces NADH and FADH2, which transfer electrons to the mitochondrial respiratory chain. The flow of electrons in this chain is coupled with the extrusion of protons from the mitochondrial matrix. When energy is needed, these protons re-enter the matrix through ATP synthase, to generate ATP. CPT-I, carnitine palmitoyl transferase I; Cyt. c, cytochrome c; G-6-P, glucose-6-phosphate; LCFA-CoA, long-chain fatty acyl-CoA; TCA cycle, tricarboxylic acid cycle.
Journal of Hepatology  , DOI: ( /j.jhep )
Copyright © 2005 European Association for the Study of the Liver Terms and Conditions

3. Fig. 2
Mitochondrial adaptation and biogenesis in skeletal muscle. Muscular exercise increases AMP, which activates AMP-activated protein kinase (AMPK), and also increases cell calcium, which activates Ca2+/calmodulin-dependent protein kinase (CaMK), to increase glucose oxidation, fat oxidation, oxidative phosphorylation (OXPHOS) and mitochondrial biogenesis (see text for further details). ACC, acetyl-CoA carboxylase; CPT-I, carnitine palmitoyl transferase I; G-6-P, glucose-6-phosphate; LCFA-CoA, long-chain fatty acyl-CoA; MCAD, medium-chain acyl-CoA dehydrogenase; mtDNA, mitochondrial DNA; mtTFA, mitochondrial transcription factor A; nDNA, nuclear DNA; NRF-1, nuclear respiratory factor-1; PGC-1, PPARγ coactivator-1; PPARα, peroxisome proliferator-activated receptor α; SDH, succinate dehydrogenase.
Journal of Hepatology  , DOI: ( /j.jhep )
Copyright © 2005 European Association for the Study of the Liver Terms and Conditions

4. Fig. 3
Insufficient mitochondrial function in the skeletal muscle of obese patients helps trigger fat accumulation and insulin resistance. In lean persons, insulin triggers tyrosine phosphorylation of insulin receptor substrate (IRS), and then phosphatidyl inositol 3-kinase (PI3K) activation and protein kinase B (PKB) activation, to finally stimulate the exocytosis of GLUT4 glucose transporter-expressing vesicles. In obese patients, lack of exercise and possibly a genetic polymorphism in PGC-1 may decrease peroxisome proliferator-activated gamma coactivator-1 (PGC-1) and nuclear respiratory factor-1 (NRF-1) expression to hamper oxidative phosphorylation (OXPHOS) and fat catabolism in myocytes. In aged persons, mitochondrial DNA (mtDNA) mutations could further aggravate this mitochondrial dysfunction. Together with excessive food intake, insufficient fat oxidation increases intramyocellular fat. Long-chain fatty acyl-CoA (LCFA-CoA) or other FFA derivatives may interrupt IRS-mediated signaling. Indeed, Jun N-terminal kinase (JNK) activation causes the serine phosphorylation and inactivation of IRS, thus blunting insulin-mediated exocytosis of the GLUT4 transporter. IR, insulin receptor; IRS-Ser-P, serine-phosphorylated IRS.
Journal of Hepatology  , DOI: ( /j.jhep )
Copyright © 2005 European Association for the Study of the Liver Terms and Conditions

5. Fig. 4
Acquired mitochondrial dysfunction can eventually blunt insulin release by pancreatic β-cells. In obese but non-diabetic subjects, glucose-derived pyruvate is oxidized by β-cell mitochondria to increase cell ATP, which closes ATP-sensitive potassium channels to depolarize the plasma membrane and open voltage-sensitive calcium channels, thus increasing cell calcium, which triggers the exocytosis of insulin-loaded vesicles. High insulin levels compensate insulin resistance in muscles, so that plasma glucose levels remain normal. Eventually, however, fat accumulation and increased uncoupling protein 2 (UCP-2) expression, and possibly also age-related mitochondrial DNA (mtDNA) mutations, may blunt ATP formation and insulin release to cause glucose intolerance and diabetes in some patients.
Journal of Hepatology  , DOI: ( /j.jhep )
Copyright © 2005 European Association for the Study of the Liver Terms and Conditions

6. Fig. 5
Homeostasis of hepatic lipids in obesity. Due to insulin resistance in adipocytes, hormone sensitive lipase (HSL) remains active and releases FFAs in the plasma, while insulin resistance in muscles cause high plasma glucose and/or insulin levels. Glucose increases hepatic carbohydrate response element binding protein (ChREBP), and insulin increases sterol regulatory element-binding protein 1c (SREBP-1c), which both induce hepatic lipogenic enzymes and increase FFA synthesis. A new steady is achieved, when this increased input of FFA is compensated for by increased mitochondrial fat oxidation and increased triglyceride secretion. Increased mitochondrial fat oxidation could be due to the increased FFA hepatic concentration, to the induction of carnitine palmitoyl transferase I (CPT-I) possibly mediated by peroxisome proliferator-activated receptor α(PPARα), and finally to decreased sensitivity of CPT-I to the inhibitory effects of malonyl-CoA. Although the expanded pool of triglycerides can lead to increased triglyceride secretion, apolipoprotein B (Apo B) secretion is instead decreased in patients with NASH, possibly due to the insulin-mediated intrahepatic degradation of Apo B.
Journal of Hepatology  , DOI: ( /j.jhep )
Copyright © 2005 European Association for the Study of the Liver Terms and Conditions

7. Fig. 6
Possible mechanisms for hepatic mitochondrial dysfunction in NASH. The increased mitochondrial oxidation of fat increases the delivery of electrons to the respiratory chain, while TNF-α-mediated permeabilization of the outer mitochondrial membrane may allow the extrusion of cytochrome c, thus partially blocking electron flow in the respiratory chain (see text for further details). The over-reduction of respiratory chain complexes increases mitochondrial ROS formation, thus triggering several vicious cycles that further block the flow of electrons in the respiratory chain (see text for further details). tBid, Truncated Bid.
Journal of Hepatology  , DOI: ( /j.jhep )
Copyright © 2005 European Association for the Study of the Liver Terms and Conditions

8. Fig. 7
Possible mechanisms for hepatic lesions in NASH. ROS may activate Fas ligand (FasL)- and TNF-α-mediated signaling to trigger permeability of mitochondrial membranes and hepatocyte apoptosis (see text for further details). The engulfment of apoptotic bodies increases TGF-β secretion by both Kupffer cells and stellate cells, and increases collagen secretion by stellate cells. Both lipid peroxidation products (LPP) and leptin cooperate to increase TGF-β formation and collagen secretion. Finally both ROS and LPP damage DNA. Together with the cell proliferation necessary to compensate for the increased cell death rate, these DNA lesions may cause somatic mutations. Due to the constant apoptotic pressure, cells that resist apoptosis and/or the control of the cell cycle may be selected, to allow development of a malignant clone.
Journal of Hepatology  , DOI: ( /j.jhep )
Copyright © 2005 European Association for the Study of the Liver Terms and Conditions