Hepatic Primary and Secondary Cholesterol Deposition and Damage in Niemann-Pick Disease

Abstract

Niemann-Pick C disease is a neurovisceral disorder caused by mutations in the NPC gene that result in systemic accumulation of intracellular cholesterol. Although neurodegeneration defines the disease's severity, in most patients it is preceded by hepatic complications such as cholestatic jaundice or hepatomegaly. To analyze the contribution of the hepatic disease in Niemann-Pick C disease progression and to evaluate the degree of primary and secondary hepatic damage, we generated a transgenic mouse with liver-selective expression of NPC1 from embryonic stages. Hepatic NPC1 re-expression did not ameliorate the onset and progression of neurodegeneration of the NPC1-null animal. However, the mice showed reduced hepatomegalia and dramatic, although not complete, reduction of hepatic cholesterol and serum bile salts, bilirubin, and transaminase levels. Therefore, hepatic primary and secondary cholesterol deposition and damage occur simultaneously during Niemann-Pick C disease progression.

Mitochondrial GSH replenishment as a potential therapeutic approach for Niemann Pick type C disease

“…Although somewhat lower than reported in some studies [34], [35], the median survival and maximal life span of our vehicle-treated Npc1 -/- colony were in line with previous reports [19], [36], [37]. As seen, intraperitoneal GSH-EE therapy significantly extended the median survival and increased the maximum life span of Npc1 -/- mice with respect to vehicle-treated Npc1 -/- mice (Fig.…”

“…While GSH-EE treatment increased mGSH levels in both liver and cerebellum, the normalization of mitochondrial function was only observed in the latter, which paralleled the improvement of Purkinje cell survival and protection against oxidative stress, likely mediating the enhanced motor coordination and increased survival. Recent observations indicated that the hepatic re-expresion of NPC1 in Npc1 -/- mice corrects the liver phenotype of the disease, although, this outcome had no impact in improving neurological symptoms or life-span extension [37]. These findings along with our observations suggest that the neurological alterations rather than the liver phenotype determine the overall progression of the juvenile form of the disease.…”

A case of Niemann-Pick disease type C with neonatal liver failure initially diagnosed as neonatal hemochromatosis

“…Also, liver transplantation was found to be ineffective at slowing the progression of NPC neurological symptoms [1]. According to another study, NPC1-null transgenic mice with liverselective re-expression of NPC1 from the embryonic stages showed ameliorated liver cholesterol deposition, but did not improve in terms of onset and progression of neurodegeneration, or mortality [11]. Although our patient's transplanted liver function also maintained a good condition, his NPC neurological symptoms advanced rapidly.…”

Lack of Annexin A6 Exacerbates Liver Dysfunction and Reduces Lifespan of Niemann-Pick Type C Protein–Deficient Mice

“…The Npc1 knock-out alleles were detected as described previously. 19 The Anxa6 knock-out alleles were detected using…”

“…18 Strikingly, we previously showed that restoration of hepatic NPC1 expression in Npc1 -/mice reduced hepatomegaly and hepatic cholesterol amounts, as well as bile salts, bilirubin, and transaminase levels in serum, without ameliorating the onset and progression of neurodegeneration. 19,20 In addition, several other endolysosomal proteins in the vicinity of NPC1 appear to influence NPC1-dependent activities and may contribute to the complex NP-C pathology. [21][22][23] Annexin A6 (ANXA6) belongs to the family of annexins 24 and is expressed in most tissues, being highly abundant in the liver 25 and brain.…”