General Information:

Id: 6,894
Diseases: Diabetes mellitus, type II - [OMIM]
Insulin resistance
Mammalia
review
Reference: Salameh TS et al.(2016) Insulin resistance, dyslipidemia, and apolipoprotein E interactions as mechanisms in cognitive impairment and Alzheimers disease Exp. Biol. Med. (Maywood) 241: 1676-1683 [PMID: 27470930]

Interaction Information:

Comment In the peripheral circulation, APOE aids in shuttling lipids between various lipoproteins. In the brain, APOE is the most abundant lipoprotein and a crucial regulator of lipid metabolism.
Formal Description
Interaction-ID: 67327

gene/protein

APOE

affects_activity of

Drugbank entries Show/Hide entries for APOE
Comment APOE mediates transport of lipoprotein particles between various cell types in the brain via carriers such as the low-density lipoprotein receptor related protein-1 (LRP-1).
Formal Description
Interaction-ID: 67339

gene/protein

APOE

increases_transport of

drug/chemical compound

Lipoprotein

in brain ; via LRP1
Drugbank entries Show/Hide entries for APOE
Comment APOE mediates transport of lipoprotein particles between various cell types in the brain via carriers such as the low-density lipoprotein receptor related protein-1 (LRP-1).
Formal Description
Interaction-ID: 67340

gene/protein

LRP1

increases_transport of

drug/chemical compound

Lipoprotein

in brain
Drugbank entries Show/Hide entries for LRP1
Comment At the blood–brain barrier (BBB), LRP-1 is involved in amyloid beta (Abeta) clearance from brain and the decrease in BBB LRP-1 levels that occurs in Alzheimer disease has been postulated as one reason why Abeta builds up in the brain.
Formal Description
Interaction-ID: 67341

gene/protein

LRP1

increases_activity of

at the blood–brain barrier
Drugbank entries Show/Hide entries for LRP1
Comment APOE is important in repairing the blood–brain barrier (BBB) after injury, and dysfunction of the BBB has been considered to be both a cause and a consequence of Alzheimer disease.
Formal Description
Interaction-ID: 67342

gene/protein

APOE

increases_activity of

Drugbank entries Show/Hide entries for APOE
Comment In humans, there are three alleles of APOE: E2, E3, and E4. The APOE4 protein is folded into a more compact structure compared to the other APOE isoforms, leading to a decreased ability to bind lipids and a higher likelihood of cleavage into neurotoxic fragments. Perivascular removal of amyloid beta (Abeta) is hindered with the expression of E4, which was shown in many in vitro studies as well as in mice expressing human E4. This decreased drainage, in turn, leads to decreased clearance of Abeta peptides and increased amyloid plaques, as well as other pathophysiologic features such as alterations in the neurovascular unit and blood–brain barrier (BBB) function.
Formal Description
Interaction-ID: 67343

gene/protein mutant

APOE (isoform E4)

decreases_activity of

Comment In humans, there are three alleles of APOE: E2, E3, and E4. The APOE4 protein is folded into a more compact structure compared to the other APOE isoforms, leading to a decreased ability to bind lipids and a higher likelihood of cleavage into neurotoxic fragments. Perivascular removal of amyloid beta (Abeta) is hindered with the expression of E4, which was shown in many in vitro studies as well as in mice expressing human E4. This decreased drainage, in turn, leads to decreased clearance of Abeta peptides and increased amyloid plaques, as well as other pathophysiologic features such as alterations in the neurovascular unit and blood–brain barrier (BBB) function.
Formal Description
Interaction-ID: 67344

gene/protein mutant

APOE (isoform E4)

decreases_activity of

Comment In humans, there are three alleles of APOE: E2, E3, and E4. The APOE4 protein is folded into a more compact structure compared to the other APOE isoforms, leading to a decreased ability to bind lipids and a higher likelihood of cleavage into neurotoxic fragments. Perivascular removal of amyloid beta (Abeta) is hindered with the expression of E4, which was shown in many in vitro studies as well as in mice expressing human E4. This decreased drainage, in turn, leads to decreased clearance of Abeta peptides and increased amyloid plaques, as well as other pathophysiologic features such as alterations in the neurovascular unit and blood–brain barrier (BBB) function.
Formal Description
Interaction-ID: 67345

gene/protein mutant

APOE (isoform E4)

increases_activity of

Comment APOE4 knock-in mice had higher levels of blood–brain barrier (BBB) breakdown in response to injury, via upregulation of the proinflammatory cyclophilin A pathway in pericytes.
Formal Description
Interaction-ID: 67346

gene/protein mutant

APOE (isoform E4)

increases_activity of

gene/protein

PPIA

Drugbank entries Show/Hide entries for PPIA
Comment The role that APOE plays in transport and clearance of molecules depends on the APOE isoform, and these transport differences may be related to differences in receptor utilization for the isoforms, with APOE4-Abeta complexes using the very low-density lipoprotein (VLDL) receptor and the other isoforms using LRP-1. These isoform specific differences may also affect how the blood-brain barrier (BBB) transports insulin, free fatty acids (FFAs), and other metabolites involved in cognitive processes.
Formal Description
Interaction-ID: 67347

gene/protein mutant

APOE (isoform E4)

interacts (colocalizes) with

gene/protein

VLDLR

Comment The role that APOE plays in transport and clearance of molecules depends on the APOE isoform, and these transport differences may be related to differences in receptor utilization for the isoforms, with APOE4-Abeta complexes using the very low-density lipoprotein (VLDL) receptor and the other isoforms using LRP-1. These isoform specific differences may also affect how the blood-brain barrier (BBB) transports insulin, free fatty acids (FFAs), and other metabolites involved in cognitive processes.
Formal Description
Interaction-ID: 67348

gene/protein mutant

APOE (isoform E2)

interacts (colocalizes) with

gene/protein

LRP1

Drugbank entries Show/Hide entries for LRP1
Comment The role that APOE plays in transport and clearance of molecules depends on the APOE isoform, and these transport differences may be related to differences in receptor utilization for the isoforms, with APOE4-Abeta complexes using the very low-density lipoprotein (VLDL) receptor and the other isoforms using LRP-1. These isoform specific differences may also affect how the blood-brain barrier (BBB) transports insulin, free fatty acids (FFAs), and other metabolites involved in cognitive processes.
Formal Description
Interaction-ID: 67349

gene/protein mutant

APOE (isoform E3)

interacts (colocalizes) with

gene/protein

LRP1

Drugbank entries Show/Hide entries for LRP1
Comment APOE4 carrier status is correlated with increased LDL and triglyceride levels, and an increased risk of heart disease.
Formal Description
Interaction-ID: 67350

gene/protein mutant

APOE (isoform E4)

increases_activity of

Comment APOE4 carrier status is correlated with increased LDL and triglyceride levels, and an increased risk of heart disease.
Formal Description
Interaction-ID: 67351

gene/protein mutant

APOE (isoform E4)

increases_activity of

Comment APOE4 carrier status is correlated with increased LDL and triglyceride levels, and an increased risk of heart disease.
Formal Description
Interaction-ID: 67352

gene/protein mutant

APOE (isoform E4)

increases_activity of

disease

Cardiovascular disease

Comment Human and experimental animal studies have confirmed a link between peripheral insulin resistance and cognitive impairment.
Formal Description
Interaction-ID: 67353

disease

Insulin resistance

affects_activity of

process

cognition

Comment There is a close association between lipid homeostasis and glucose regulation.
Formal Description
Interaction-ID: 67354

affects_activity of

Comment Elevated lipid levels can chronically impact insulin secretion by the beta-cell in the pancreas.
Formal Description
Interaction-ID: 67355

phenotype

hyperlipidemia

decreases_activity of

Comment Chronic peripheral hyperinsulinemia serves to reduce transport of insulin into the brain.
Formal Description
Interaction-ID: 67356

decreases transport of

complex/PPI

Insulin

into the brain
Comment Intranasal insulin improves cognition.
Formal Description
Interaction-ID: 67357

environment

intranasal insulin

increases_activity of

process

cognition

Comment APOE4 carriers showed poorer responses to intranasal insulin treatment compared to patients who were E4 noncarriers.
Formal Description
Interaction-ID: 67358

gene/protein mutant

APOE (isoform E4)

affects_activity of

environment

intranasal insulin

Comment Studies investigating the role of lipids in the brain have revealed abnormal lipid metabolism as an important pathophysiological process in the development of Alzheimer disease (AD). Diets consisting of an increased consumption of saturated and trans-fats incur an increased incidence of AD, while diets rich in healthy fats are protective.
Formal Description
Interaction-ID: 67359

affects_activity of

Comment Studies investigating the role of lipids in the brain have revealed abnormal lipid metabolism as an important pathophysiological process in the development of Alzheimer disease (AD). Diets consisting of an increased consumption of saturated and trans-fats incur an increased incidence of AD, while diets rich in healthy fats are protective.
Formal Description
Interaction-ID: 67360

increases_activity of

Comment Studies investigating the role of lipids in the brain have revealed abnormal lipid metabolism as an important pathophysiological process in the development of Alzheimer disease (AD). Diets consisting of an increased consumption of saturated and trans-fats incur an increased incidence of AD, while diets rich in healthy fats are protective.
Formal Description
Interaction-ID: 67363

environment

high-saturated-fat diet

increases_activity of

Comment Lipid metabolism is closely associated with the processing of APP, which results in increased production of Abeta.
Formal Description
Interaction-ID: 67364
Comment APOE4 positive individuals have more exaggerated plasma lipid changes after high-fat diet intake.
Formal Description
Interaction-ID: 67365

gene/protein mutant

APOE (isoform E4)

affects_activity of

Comment Animal studies have shown diets high in saturated fats or cholesterol increase levels of Abeta and decrease brain insulin levels.
Formal Description
Interaction-ID: 67366

environment

high-saturated-fat diet

decreases_quantity of

complex/PPI

Insulin

in brain
Comment Animal studies have shown diets high in saturated fats or cholesterol increase levels of Abeta and decrease brain insulin levels.
Formal Description
Interaction-ID: 67367

environment

high-saturated-fat diet

increases_quantity of

gene/protein

Amyloid beta peptide

in brain
Comment Insulin showed decreased transport across the blood-brain barier (BBB) in diet-induced obese mice and increased transport in a state of starvation. The transport of insulin is influenced by the level of triglycerides.
Formal Description
Interaction-ID: 67368

affects transport of

complex/PPI

Insulin

across the blood-brain barrier
Comment Insulin in the brain acts as a satiety factor. It does this through a number of mechanisms including reducing appetite and decreasing body mass.
Formal Description
Interaction-ID: 67369

complex/PPI

Insulin

increases_activity of

phenotype

increased sense of satiety

Comment Insulin in the brain acts as a satiety factor. It does this through a number of mechanisms including reducing appetite and decreasing body mass.
Formal Description
Interaction-ID: 67370

complex/PPI

Insulin

increases_activity of

Comment Insulin in the brain acts as a satiety factor. It does this through a number of mechanisms including reducing appetite and decreasing body mass.
Formal Description
Interaction-ID: 67371

complex/PPI

Insulin

increases_activity of

Comment Similar results have been observed with ghrelin, where its transport across the blood-brain barrier (BBB) was decreased with obesity and increased with triglycerides. Ghrelin is known to have an effect on cognition.
Formal Description
Interaction-ID: 67372

disease

Obesity

decreases transport of

gene/protein

Ghrelin

across the blood-brain barrier
Comment Similar results have been observed with ghrelin, where its transport across the blood-brain barrier (BBB) was decreased with obesity and increased with triglycerides. Ghrelin is known to have an effect on cognition.
Formal Description
Interaction-ID: 67373

increases_transport of

gene/protein

Ghrelin

across the blood-brain barrier
Comment Similar results have been observed with ghrelin, where its transport across the blood-brain barrier (BBB) was decreased with obesity and increased with triglycerides. Ghrelin is known to have an effect on cognition.
Formal Description
Interaction-ID: 67374

gene/protein

Ghrelin

affects_activity of

process

cognition

Comment Triglycerides do not enhance all peptide transport across the blood-brain barrier (BBB). In a study examining leptin transport during starvation and diet-induced obesity, it was observed that leptin transport was decreased in both conditions. A commonality between these two states is the increased levels of triglycerides in circulation. The findings of this study identified triglycerides as a factor inhibiting leptin transport during starvation. Also, the authors showed that increasing triglyceride levels with diet or fasting in normal or obese mice had an inverse effect on leptin transport; and that lowering triglycerides using gemfibrozil reversed the impairment in leptin transport. These results demonstrate that triglycerides are involved in peripheral leptin resistance observed during starvation and obesity.
Formal Description
Interaction-ID: 67375

decreases transport of

gene/protein

LEP

across the blood-brain barrier
Comment Triglycerides do not enhance all peptide transport across the blood-brain barrier (BBB). In a study examining leptin transport during starvation and diet-induced obesity, it was observed that leptin transport was decreased in both conditions. A commonality between these two states is the increased levels of triglycerides in circulation. The findings of this study identified triglycerides as a factor inhibiting leptin transport during starvation. Also, the authors showed that increasing triglyceride levels with diet or fasting in normal or obese mice had an inverse effect on leptin transport; and that lowering triglycerides using gemfibrozil reversed the impairment in leptin transport. These results demonstrate that triglycerides are involved in peripheral leptin resistance observed during starvation and obesity.
Formal Description
Interaction-ID: 67376

affects_activity of

phenotype

leptin resistance

Comment Leptin has been shown to play an important role in memory and learning by influencing the synaptic plasticity of hippocampal neurons as well as long-term potentiation and depression. Leptin levels have also been shown to be inversely correlated with AD risk and increased leptin appears to be protective against dementia in adults.
Formal Description
Interaction-ID: 67377

gene/protein

LEP

increases_activity of

process

memory

Comment Leptin has been shown to play an important role in memory and learning by influencing the synaptic plasticity of hippocampal neurons as well as long-term potentiation and depression. Leptin levels have also been shown to be inversely correlated with AD risk and increased leptin appears to be protective against dementia in adults.
Formal Description
Interaction-ID: 67378

gene/protein

LEP

increases_activity of

process

learning

Comment Leptin has been shown to play an important role in memory and learning by influencing the synaptic plasticity of hippocampal neurons as well as long-term potentiation and depression. Leptin levels have also been shown to be inversely correlated with AD risk and increased leptin appears to be protective against dementia in adults.
Formal Description
Interaction-ID: 67379

gene/protein

LEP

increases_activity of

Comment Leptin has been shown to play an important role in memory and learning by influencing the synaptic plasticity of hippocampal neurons as well as long-term potentiation and depression. Leptin levels have also been shown to be inversely correlated with AD risk and increased leptin appears to be protective against dementia in adults.
Formal Description
Interaction-ID: 67380

gene/protein

LEP

increases_activity of

Comment Leptin has been shown to play an important role in memory and learning by influencing the synaptic plasticity of hippocampal neurons as well as long-term potentiation and depression. Leptin levels have also been shown to be inversely correlated with AD risk and increased leptin appears to be protective against dementia in adults.
Formal Description
Interaction-ID: 67381

gene/protein

LEP

increases_activity of

Comment Leptin has been shown to play an important role in memory and learning by influencing the synaptic plasticity of hippocampal neurons as well as long-term potentiation and depression. Leptin levels have also been shown to be inversely correlated with AD risk and increased leptin appears to be protective against dementia in adults.
Formal Description
Interaction-ID: 67382

gene/protein

LEP

decreases_activity of

disease

Dementia

Comment There are a number of peptides in the brain that have been shown to stimulate ingestive behavior; for example, the over-consumption of food, which leads to the development of obesity. These peptides include galanin (GAL), the opioid peptides enkephalin (ENK) and dynorphin (DYN), and the orexins (ORX). Investigation of these peptides demonstrates that they are highly responsive to changes in diet and nutrients. Studies have shown that endogenous gene and protein expressions for GAL, ENK, DYN, and ORX in the periventricular nucleus and perifornical lateral hypothalamus are closely related to dietary fat, showing a positive correlation with the amount of fat consumed.
Formal Description
Interaction-ID: 67383

gene/protein

Galanin

increases_activity of

Comment There are a number of peptides in the brain that have been shown to stimulate ingestive behavior; for example, the over-consumption of food, which leads to the development of obesity. These peptides include galanin (GAL), the opioid peptides enkephalin (ENK) and dynorphin (DYN), and the orexins (ORX). Investigation of these peptides demonstrates that they are highly responsive to changes in diet and nutrients. Studies have shown that endogenous gene and protein expressions for GAL, ENK, DYN, and ORX in the periventricular nucleus and perifornical lateral hypothalamus are closely related to dietary fat, showing a positive correlation with the amount of fat consumed.
Formal Description
Interaction-ID: 67384

gene/protein

Enkephalin

increases_activity of

Comment There are a number of peptides in the brain that have been shown to stimulate ingestive behavior; for example, the over-consumption of food, which leads to the development of obesity. These peptides include galanin (GAL), the opioid peptides enkephalin (ENK) and dynorphin (DYN), and the orexins (ORX). Investigation of these peptides demonstrates that they are highly responsive to changes in diet and nutrients. Studies have shown that endogenous gene and protein expressions for GAL, ENK, DYN, and ORX in the periventricular nucleus and perifornical lateral hypothalamus are closely related to dietary fat, showing a positive correlation with the amount of fat consumed.
Formal Description
Interaction-ID: 67385

gene/protein

Dynorphin

increases_activity of

Comment There are a number of peptides in the brain that have been shown to stimulate ingestive behavior; for example, the over-consumption of food, which leads to the development of obesity. These peptides include galanin (GAL), the opioid peptides enkephalin (ENK) and dynorphin (DYN), and the orexins (ORX). Investigation of these peptides demonstrates that they are highly responsive to changes in diet and nutrients. Studies have shown that endogenous gene and protein expressions for GAL, ENK, DYN, and ORX in the periventricular nucleus and perifornical lateral hypothalamus are closely related to dietary fat, showing a positive correlation with the amount of fat consumed.
Formal Description
Interaction-ID: 67386

gene/protein

Orexin

increases_activity of

Comment There are a number of peptides in the brain that have been shown to stimulate ingestive behavior; for example, the over-consumption of food, which leads to the development of obesity. These peptides include galanin (GAL), the opioid peptides enkephalin (ENK) and dynorphin (DYN), and the orexins (ORX). Investigation of these peptides demonstrates that they are highly responsive to changes in diet and nutrients. Studies have shown that endogenous gene and protein expressions for GAL, ENK, DYN, and ORX in the periventricular nucleus and perifornical lateral hypothalamus are closely related to dietary fat, showing a positive correlation with the amount of fat consumed.
Formal Description
Interaction-ID: 67387

environment

high-fat diet

increases_quantity of

gene/protein

Galanin

Comment There are a number of peptides in the brain that have been shown to stimulate ingestive behavior; for example, the over-consumption of food, which leads to the development of obesity. These peptides include galanin (GAL), the opioid peptides enkephalin (ENK) and dynorphin (DYN), and the orexins (ORX). Investigation of these peptides demonstrates that they are highly responsive to changes in diet and nutrients. Studies have shown that endogenous gene and protein expressions for GAL, ENK, DYN, and ORX in the periventricular nucleus and perifornical lateral hypothalamus are closely related to dietary fat, showing a positive correlation with the amount of fat consumed.
Formal Description
Interaction-ID: 67388

environment

high-fat diet

increases_quantity of

gene/protein

Enkephalin

Comment There are a number of peptides in the brain that have been shown to stimulate ingestive behavior; for example, the over-consumption of food, which leads to the development of obesity. These peptides include galanin (GAL), the opioid peptides enkephalin (ENK) and dynorphin (DYN), and the orexins (ORX). Investigation of these peptides demonstrates that they are highly responsive to changes in diet and nutrients. Studies have shown that endogenous gene and protein expressions for GAL, ENK, DYN, and ORX in the periventricular nucleus and perifornical lateral hypothalamus are closely related to dietary fat, showing a positive correlation with the amount of fat consumed.
Formal Description
Interaction-ID: 67389

environment

high-fat diet

increases_quantity of

gene/protein

Dynorphin

Comment There are a number of peptides in the brain that have been shown to stimulate ingestive behavior; for example, the over-consumption of food, which leads to the development of obesity. These peptides include galanin (GAL), the opioid peptides enkephalin (ENK) and dynorphin (DYN), and the orexins (ORX). Investigation of these peptides demonstrates that they are highly responsive to changes in diet and nutrients. Studies have shown that endogenous gene and protein expressions for GAL, ENK, DYN, and ORX in the periventricular nucleus and perifornical lateral hypothalamus are closely related to dietary fat, showing a positive correlation with the amount of fat consumed.
Formal Description
Interaction-ID: 67390

environment

high-fat diet

increases_quantity of

gene/protein

Orexin