Lack Of The Lysosomal Membrane Protein, Glmp, In Mice Results In Metabolic Dysregulation In Liver

Ablation of glycosylated lysosomal membrane protein (GLMP, formerly known as NCU-G1) has been shown to cause chronic liver injury which progresses into liver fibrosis in mice. Both lysosomal dysfunction and chronic liver injury can cause metabolic dysregulation. Glmp(gt/gt) mice (formerly known as Ncu-g1(gt/gt)mice) were studied between 3 weeks and 9 months of age. Body weight gain and feed efficiency of Glmpgt/gt mice were comparable to wild type siblings, only at the age of 9 months the Glmp(gt/gt) siblings had significantly reduced body weight. Reduced size of epididymal fat pads was accompanied by hepatosplenomegaly in Glmp(gt/gt) mice. Blood analysis revealed reduced levels of blood glucose, circulating triacylglycerol and non-esterified fatty acids in Glmp(gt/gt) mice. Increased flux of glucose, increased de novo lipogenesis and lipid accumulation were detected in Glmp(gt/gt) primary hepatocytes, as well as elevated triacylglycerol levels in Glmp(gt/gt) liver homogenates, compared to hepatocytes and liver from wild type mice. Gene expression analysis showed an increased expression of genes involved in fatty acid uptake and lipogenesis in Glmp(gt/gt) liver compared to wild type. Our findings are in agreement with the metabolic alterations observed in other mouse models lacking lysosomal proteins, and with alterations characteristic for advanced chronic liver injury.