Activation of lipoprotein lipase in cardiac myocytes by glycosylation requires trimming of glucose residues in the endoplasmic reticulum

Carroll, Rogayah; Ben-Zeev, Osnat; Doolittle, Mark H.; Severson, David L.

doi:10.1042/bj2850693

Cited by 24 publications

(18 citation statements)

References 28 publications

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“…LPL deficiency, inherited as an autosomal recessive trait, accounts for most cases of familial hyperchylomicronemia (426). Most of these LPL processing steps occur in the ER (430,431). Most of these LPL processing steps occur in the ER (430,431).…”

Section: Ersds Affecting Lipoprotein Metabolismmentioning

confidence: 99%

Endocrinopathies in the Family of Endoplasmic Reticulum (ER) Storage Diseases: Disorders of Protein Trafficking and the Role of ER Molecular Chaperones*

Kim¹,

Arvan²

1998

Endocrine Reviews

129

106

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From the studies described in this review, it is clear that structural information dictates not only the functional properties of exportable proteins, but also their ability to be transported in the intracellular secretory pathway. In ERSDs, the precise nature of the defect determines both the severity of the phenotype and the mode of inheritance. To our knowledge, all genetically inherited ERSDs are attributable to mutations in the coding sequence of exportable proteins; thus far, with the exception of abetalipoproteinemia (see Section IV.D), no mutations in ER chaperones (other than those that scientists have genetically engineered) have been reported as the cause of spontaneous disease. The elevations of ER chaperones in ERSDs may differ between mutations, between tissues, between individual patients, and between different physiological states (i.e., such as before and after hormone replacement therapy) in the same patient. Thus, measurement of ER chaperone levels plays an important diagnostic role, but probably should not be used as the sole basis to classify these illnesses. Moreover, because mutant secretory proteins have been reported to occur in virtually every organ system, ERSDs are more readily classified at the cell biological level, by the responses of the cells that actually synthesize the secretory protein, rather than the hormone deficiency associated with the illness at the end-organ level. With these ideas in mind, we present a schematic view in Fig. 4. According to this schema, all ERSDs begin with ER retention of the affected proteins or their subunits. Mutants may then be divided into two groups: type A, where the biological activity is preserved although the protein is transport-deficient; and type B, where the mutant has no potential for functional activity. Both categories include both recessive and dominant mutations. The primary clinical difference between these two classes is that type A ERSDs may be amenable to therapies designed to down-regulate the quality control of ER export so that potentially functional molecules can escape the ER and reach their intended intracellular destination. In both types of ERSDs, in most cases, the retained mutant protein is efficiently degraded in the ER (subtypes A-I and B-I). In these cases, the predominant, global phenotypes involve the symptoms and signs of hormone deficiency. However, careful biochemical and cell biological studies reveal various abnormalities in glandular function, typically including the elevation of the levels of one or more ER chaperones. As described in Section I.C, such elevations are a consequence of chronic adaptation to the presence of unfolded mutant secretory protein (the synthesis of which is stimulated all the more by endocrine feedback loops). As described in Section III, the elevated chaperones appear to be integrally related to the ER retention as well as perhaps the ERAD process that removes the misfolded proteins. In these cases, the ER compartment may expand, but the secretory cells are likely to survive. In the ...

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Section: Ersds Affecting Lipoprotein Metabolismmentioning

confidence: 99%

Endocrinopathies in the Family of Endoplasmic Reticulum (ER) Storage Diseases: Disorders of Protein Trafficking and the Role of ER Molecular Chaperones*

Kim¹,

Arvan²

1998

Endocrine Reviews

129

106

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“…Monoclonal antibody to bovine milk LPL (5D2; [28]) was coupled to Affigel 10 beads (0.7 ,ug of antibody/,ul of gel matrix). Control and diabetic cardiomyocytes (106 cells/ml in Joklik medium) were suspended into a modified Krebs-Ringer buffer [29], and labelled with 0.33 mCi/ml [35S]methionine at 37 'C under 02/C02 (19: 1). After the indicated pulse times, aliquots (1 ml) were removed and centrifuged at 15000 g for 10 s; the cell pellets were then homogenized in 1 ml of lysis buffer [29].…”

Section: Lpl Synthesis and Turnovermentioning

confidence: 99%

“…Control and diabetic cardiomyocytes (106 cells/ml in Joklik medium) were suspended into a modified Krebs-Ringer buffer [29], and labelled with 0.33 mCi/ml [35S]methionine at 37 'C under 02/C02 (19: 1). After the indicated pulse times, aliquots (1 ml) were removed and centrifuged at 15000 g for 10 s; the cell pellets were then homogenized in 1 ml of lysis buffer [29]. After centrifugation, 0.5 ml of the clear supernatants were immunoprecipitated overnight with 20 ,tg of Affigel-5D2 monoclonal antibody matrix.…”

Section: Lpl Synthesis and Turnovermentioning

confidence: 99%

Post-transcriptional mechanisms are responsible for the reduction in lipoprotein lipase activity in cardiomyocytes from diabetic rat hearts

Carroll

Liu

Severson

1995

Biochemical Journal

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Lipoprotein lipase (LPL) activity is reduced in cardiomyocytes from rat hearts following the acute (4-5 day) induction of diabetes with 100 mg/kg streptozotocin. The molecular basis for this inhibitory effect of diabetes on LPL activity was investigated by measuring steady-state LPL mRNA content and the synthesis and turnover of LPL protein ([35S]methionine incorporation into immunoprecipitable LPL protein in pulse and pulse-chase experiments) in control and diabetic cardiomyocytes. LPL activity was reduced to approx. 50% of control in diabetic cardiomyocytes, but LPL mRNA levels and turnover (degradation) of newly synthesized LPL were unchanged. Synthesis of total protein and LPL were reduced to 72% and 71% of control respectively; therefore, relative rates of LPL synthesis were the same in control and diabetic cardiomyocytes. The diabetes-induced reduction in LPL synthesis was accompanied by a decrease in LPL mass to 78% of control, and a decrease in enzyme specific activity (0.48 to 0.33 m-unit/ng of LPL protein) since the decline in catalytic activity was greater than the decrease in LPL synthesis and mass. Thus, post-transcriptional mechanisms involving a reduction in LPL synthesis as part of a generalized decrease in total protein synthesis, together with a post-translational mechanism(s) that result in accumulation of inactive LPL protein, are responsible for the decreased LPL activity in cardiomyocytes from diabetic rat hearts.

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“…In adipose tissue and muscle, the tissues in which LPL synthesis has been most closely studied, there is a large pool of enzyme within adipocytes, much of which is not active (Pradines-Figueres et al 1990). Within the parenchymal cell LPL is post-translationally modified, by glycosylation and further remodelling of the glycosyl chains (Carroll et al 1992), before the active enzyme is exported to the endothelial cells. Within adipose tissue in particular it appears that a large proportion of the intracellular enzyme is destined for degradation without export, and activation of the enzyme (i.e.…”

Section: Lipoprotein Lipase: Backgroundmentioning

confidence: 99%

Lipoprotein lipase and the disposition of dietary fatty acids

1998

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Lipoprotein lipase (EC 3.1.1.34; LPL) is a key enzyme regulating the disposal of lipid fuels in the body. It is expressed in a number of peripheral tissues including adipose tissue, skeletal and cardiac muscle and mammary gland. Its role is to hydrolyse triacylglycerol (TG) circulating in the TG-rich lipoprotein particles in order to deliver fatty acids to the tissue. It appears to act preferentially on chylomicron-TG, and therefore may play a particularly important role in regulating the disposition of dietary fatty acids. LPL activity is regulated according to nutritional state in a tissue-specific manner according to the needs of the tissue for fatty acids. For instance, it is highly active in lactating mammary gland; in white adipose tissue it is activated in the fed state and suppressed during fasting, whereas the reverse is true in muscle. Such observations have led to the view of LPL as a metabolic gatekeeper, especially for dietary fatty acids. However, closer inspection of its action in white adipose tissue reveals that this picture is only partially true. Normal fat deposition in adipose tissue can occur in the complete absence of LPL, and conversely, if LPL activity is increased by pharmacological means, increased fat storage does not necessarily follow. LPL appears to act as one member of a series of metabolic steps which are regulated in a highly coordinated manner. In white adipose tissue, it is clear that there is a major locus of control of fatty acid disposition downstream from LPL. This involves regulation of the pathway of fatty acid uptake and esterification, and appears to be regulated by a number of factors including insulin, acylation-stimulating protein and possibly leptin.

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Activation of lipoprotein lipase in cardiac myocytes by glycosylation requires trimming of glucose residues in the endoplasmic reticulum

Cited by 24 publications

References 28 publications

Endocrinopathies in the Family of Endoplasmic Reticulum (ER) Storage Diseases: Disorders of Protein Trafficking and the Role of ER Molecular Chaperones*

Endocrinopathies in the Family of Endoplasmic Reticulum (ER) Storage Diseases: Disorders of Protein Trafficking and the Role of ER Molecular Chaperones*

Post-transcriptional mechanisms are responsible for the reduction in lipoprotein lipase activity in cardiomyocytes from diabetic rat hearts

Lipoprotein lipase and the disposition of dietary fatty acids

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