Abetalipoproteinemia. New insights into lipoprotein assembly and vitamin E metabolism from a rare genetic disease

Loss of both phospholipid and triglyceride transfer activities of microsomal triglyceride transfer protein in abetalipoproteinemia

“…During the fi rst and second decade, the fi rst symptoms to be noticed are fat malabsorption, steatorrhea, and failure to thrive. The other ramifi cations of the disease are fat-soluble vitamin defi ciency, specifi cally vitamin E ( 19 ) and vitamin A, as apoB-containing lipoproteins distribute these vitamins to the peripheral tissues. The most prominent and debilitating clinical manifestations of ABL are neurological disorders caused by the deficiency of vitamin E and progressive degeneration of the central nervous system, leading to death.…”

Cp-346086

“…A similar phenotype is observed in MTP knockout mice (23,30). Abetalipoproteinemia, however, represents an extreme example of MTP inhibition and is not without its clinical sequelae, all of which presumably are related directly or indirectly to fat malabsorption (steatorrhea), vitamin malabsorption, and hepatic and intestinal steatosis (29,31). A less severe, and probably more relevant, example of the consequences of therapeutic MTP inhibition is a related genetic disease, hypobetalipoproteinemia, caused by mutations in apoB (32).…”

“…These issues include those related to the potential for adverse effects associated with mechanismbased fat malabsorption (steatorrhea), fat-soluble vitamin (e.g., vitamin A, vitamin E, vitamin K) malabsorption, and fat accumulation in the liver and intestine (31), all of which have been observed preclinically with various MTP by guest, on May 10, 2018 www.jlr.org Downloaded from inhibitors (see below). Indeed, such adverse findings are also observed in patients with abetalipoproteinemia (29,31) and thus have the potential to occur in clinical trials with MTP inhibition, especially if the degree of inhibition is marked or the exposure to inhibitor is prolonged.…”

“…These issues include those related to the potential for adverse effects associated with mechanismbased fat malabsorption (steatorrhea), fat-soluble vitamin (e.g., vitamin A, vitamin E, vitamin K) malabsorption, and fat accumulation in the liver and intestine (31), all of which have been observed preclinically with various MTP by guest, on May 10, 2018 www.jlr.org Downloaded from inhibitors (see below). Indeed, such adverse findings are also observed in patients with abetalipoproteinemia (29,31) and thus have the potential to occur in clinical trials with MTP inhibition, especially if the degree of inhibition is marked or the exposure to inhibitor is prolonged. In general, however, the preclinical adverse effect profiles of MTP inhibitors have been promising and related mainly to gastrointestinal disturbances, presumably associated with steatorrhea and/or intestinal mucosal lipid accumulation and liver function abnormalities, estimated by elevations of plasma aspartate aminotransferase (AST) and ALT levels, which are presumed to be related to hepatic lipid accumulation.…”

“…Also, although vitamin deficiencies are a hallmark of abetalipoproteinemia (29,31), to date no evidence for vitamin deficiencies has been noted in subjects treated with MTP inhibitors. For example, 4 week clinical studies with efficacious concentrations of BAY 13-9952 have demonstrated only minor changes in circulating vitamin A levels (55).…”