Lack of the Lysosomal Membrane Protein, GLMP, in Mice Results in Metabolic Dysregulation in Liver

Abstract

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. Glmpgt/gt mice (formerly known as Ncu-g1gt/gtmice) 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 Glmpgt/gt siblings had significantly reduced body weight. Reduced size of epididymal fat pads was accompanied by hepatosplenomegaly in Glmpgt/gt mice. Blood analysis revealed reduced levels of blood glucose, circulating triacylglycerol and non-esterified fatty acids in Glmpgt/gt mice. Increased flux of glucose, increased de novo lipogenesis and lipid accumulation were detected in Glmpgt/gt primary hepatocytes, as well as elevated triacylglycerol levels in Glmpgt/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 Glmpgt/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.

Age-dependent development of liver fibrosis in Glmp gt/gt mice

“…In wild-type mice Glmp expression increased rapidly after birth, coinciding with the rapid growth of both liver and the animal. In a recent report, we showed that the liver/body weight ratio more than doubled in the first 2 weeks of life [ 39 ]. In the early phase of life, the liver metabolism has to adapt to lactation and in this scenario, the lack of GLMP presumably causes the chronic liver injury leading to the observed fibrosis.…”

“…A study conducted by Nelson et al [ 56 ] showed that iron deposition specifically in Kupffer cells was associated with metabolic liver injury. In a recent study, we have demonstrated dysregulation of glucose and lipid metabolism in Glmp gt/gt liver and isolated primary hepatocytes [ 39 ]. The absence of signs of liver injury in newborn Glmp gt/gt mice suggests that GLMP may not be essential in mouse prenatal life.…”

“…Based on the data presented here showing that hepatocyte proliferation and oval cell proliferation occur simultaneously, we hypothesize that four factors may contribute to the observed fibrosis: the demand for high activity in metabolic pathways after birth, increased influx of LPS from the intestine, the demand for liver growth to accompany the growth of the animal, and the increased need to replace damaged hepatocytes. The high demand for metabolic activity, especially with regard to lipids, which occurs after birth, generates ROS and oxidative stress in Glmp gt/gt hepatocytes due to their reduced lipid metabolic capacity [ 39 ]. This impairs their proliferation potential and leads to apoptosis and influx of inflammatory cells from circulation [ 17 , 19 , 20 ].…”

SNV discovery and functional candidate gene identification for milk composition based on whole genome resequencing of Holstein bulls with extremely high and low breeding values

“…C3H1orf85 encodes glycosylated lysosomal membrane protein and was also known as GLMP . Data indicated that increased flux of glucose, increased de novo lipogenesis and lipid accumulation were detected in lysosomal protein NCU-G1 ( GLMP ) gt/gt primary hepatocytes[72]. Compared with the wild-type myotubes, myotubes from GLMP (gt/gt) mice metabolized glucose faster and had a larger pool of intracellular glycogen, while oleic acid uptake, storage and oxidation were significantly reduced [73].…”

Cortical atrophy and hypofibrinogenemia due to FGG and TBCD mutations in a single family: a case report

“…Exome sequencing revealed homozygous variants in four candidate genes including, GLMP , SYNPO2 , FGG and TBCD (Additional file 1 : Table S2). GLMP encodes glycosylated lysosomal membrane protein which has role in the metabolic regulation of liver [ 15 ]. We excluded this variant since the patient did not have any liver disease.…”