Pathophysiology of Lipodystrophy Mechanisms of Lipodystrophy The Effects of Protease Inhibitors

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Different hypotheses have been put forward to explain the putative mechanism of HAART drugs in the development of lipodystrophy syndrome [116-120,122-124,126,134,141,147-152]. The first postulates that PIs primarily block cytochrome P450, which is involved in fat metabolism. The second postulates an interaction between PIs and human proteins. HIV protease has a sequence homology of 12 amino acids with two human proteins playing an important role in fat metabolism, namely, LDL-receptor-related protein (LRP) and cytoplasmic retinoic-acid-binding protein type-1 (CRABP-1). PIs inhibit both HIV protease and these two proteins. Inhibition of LRP leads to a reduction in the absorption of fatty acids by capillary endothelium and liver cells. This causes elevated serum triglycerides, visceral fat accumulation, buffalo humps, bull neck, insulin resistance, type II diabetes, breast hypertrophy, etc. Inhibition of CRABP-1 and cytochrome P450 3A isoform results in decreased cell differentiation and cell death (apoptosis), with reduced triglyceride storage and release. Under normal conditions retinoic acid in peripheral adipocytes binds to CRABP-1 and is then transformed, by a catalysed reaction with cytochrome P450 3A isoform, into cis-9-retinoic-acid, which activates the retinoic X receptor (RXR). Another suggested mechanism is alteration of the expression of steroid regulatory element-binding protein-1 (SREBP-1) in adipocytes and in the liver by PIs [153].

Several other PI-related disturbances have been proposed to explain dyslipidaemia and lipodystrophy, such as inhibition of LPL [154] and defects of lamin A/C (LMNA) and PPARG genes, which are associated with autosomal dominant familial partial lipodystrophies [148].

In capillary vessel endothelium, exposure of hepatocytes and adipocytes to PIs can result in the

Lipodystrophy

Fig. 10. Some clinical examples of AIDS related cachexia: 1,2, 3 Three cases of massive loss of subcutanoeus fat and muscles in torax, arms, abdomen and prescalenic regions (frontal view). 4, 5 Patients having lost dorso-cervical muscular mass and fat, with evidence of scapular and clavicular bones (lateral and dorsal view). 6 Example of extreme cachexia with disappearance of tenar and ipotenar pads and hypotrophy of metacarpal muscles

Fig. 10. Some clinical examples of AIDS related cachexia: 1,2, 3 Three cases of massive loss of subcutanoeus fat and muscles in torax, arms, abdomen and prescalenic regions (frontal view). 4, 5 Patients having lost dorso-cervical muscular mass and fat, with evidence of scapular and clavicular bones (lateral and dorsal view). 6 Example of extreme cachexia with disappearance of tenar and ipotenar pads and hypotrophy of metacarpal muscles

Lipoatrophy Extreme

Fig. 11. Clinical cases of lipodystrophy syndrome in HIV patients with subcutaneous peripheral lipoatrophy and/or localised fat accumulation. 1 Patient with generalised peripheral lipoatrophy. 2,3 Example of atrophy of fat pads of the face (Bichat pads loss). 4 Loss of subcutaneous fat and prominence of veins and muscles in the legs. 5 Atrophy of fat and muscles in the knee region. 6 Regional fat atrophy in the buttock region. 7 Increased abdominal fat in a patient with associated peripheral lipoatrophy. 8 Typical buffalo hump and increase of neck fat. 9 Enlargement of the breast due to accumulation of subcutaneous and mammary fat. 10,11 Bilateral benign symmetric lipomatosis with enlargement of breast and bullneck

Fig. 11. Clinical cases of lipodystrophy syndrome in HIV patients with subcutaneous peripheral lipoatrophy and/or localised fat accumulation. 1 Patient with generalised peripheral lipoatrophy. 2,3 Example of atrophy of fat pads of the face (Bichat pads loss). 4 Loss of subcutaneous fat and prominence of veins and muscles in the legs. 5 Atrophy of fat and muscles in the knee region. 6 Regional fat atrophy in the buttock region. 7 Increased abdominal fat in a patient with associated peripheral lipoatrophy. 8 Typical buffalo hump and increase of neck fat. 9 Enlargement of the breast due to accumulation of subcutaneous and mammary fat. 10,11 Bilateral benign symmetric lipomatosis with enlargement of breast and bullneck disturbed absorption of fatty acids through LPL inhibition [155]. All these alterations increase plasma triglycerides, resulting in central/visceral adiposity, insulin resistance leading to type II diabetes, and breast hypertrophy. We have been working on this hypothesis since our early studies on the mechanisms of cachexia, in which TNF was found to inhibit and progestin derivatives to stimulate LPL, the key enzyme of lipid metabolism [2, 156,157].

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