Abetalipoproteinemia induced by overexpression of ORP150 in mice

ORP150 is an endoplasmic-resident, hypoxic stress-induced protein, but little is known about the effects of its systemic overexpression. We have produced a transgenic strain of mice that overexpress ORP150 (ORP-Tg mice). These mice exhibit severe growth retardation concomitant with vacuolar degeneration in the heart. To investigate the cause of the observed growth retardation in response to ORP150 overexpression, we conducted a clinical evaluation of the ORP-Tg mice. Blood analysis showed significantly lower concentrations of serum triglyceride, cholesterol, glucose and insulin. The triglyceride components that were reduced in ORP-Tg mice were localized mainly at the origin and in the pre-beta fraction on agarose gel electrophoresis, corresponding to chylomicrons and very low-density lipoproteins. A lipid-loading test of ORP-Tg mice revealed reduced triglyceride uptake, which mainly was due to suppressed uptake of very low-density lipoproteins. An intraperitoneal glucose tolerance test indicated that the ORP-Tg mice have a significantly higher rate of glucose degradation. These findings suggest that overexpression of ORP150 in mice leads to abetalipoproteinemia with alteration of glucose and lipid metabolism. These data could provide clues for a therapeutic target of dyslipidemia or diabetes.