Question 1

The omega-3 class of polyunsaturated fatty acids (PUFAs) exerts potent effects on neural development, cardiovascular function, and inflammation. The most active omega-3 PUFAs are DHA and EPA. These PUFA are precursors for which of the following class of biologically active lipids?

A) gangliosides
B) leukotrienes
C) prostaglandins
D) resolvins
E) thromboxanes

resolvins

Accepted Answer

DHA and EPA are precursors for resolvins, which are a class of bioactive lipids involved in resolving inflammation.  The resolvins (Rv) have antiinflammatory actions that lead to the resolution of the inflammatory processes, hence the derivation of their names as resolvins (resolution phase interaction products). The resolvins are synthesized either from eicosapentaenoic acid (EPA) or from docosahexaenoic (DHA). The D-series resolvins are derived from DHA and the E-series from EPA.

Question 2

You are testing the activity of a fatty acid analog for efficacy in the treatment of the hyperglycemia associated with Type 2 diabetes. You find that inclusion of the compound in the diet of these test subjects results in an increased release of the gut hormone GLP-1. Which of the following fatty acid-binding receptors is most likely activated by your compound in the gut of the test subjects accounting for the observed response?

A) GPR35
B) GPR40
C) GPR41
D) GPR55
E) GPR120

GPR120

Accepted Answer

GPR120 is a fatty acid-binding receptor known to mediate the release of GLP-1 in the gut, which can help regulate glucose levels and improve insulin sensitivity, making it relevant in the context of Type 2 diabetes treatment.  GPR120 is specifically activated by long-chain nonesterified fatty acids (NEFAs), in particular in the intestines by α-linolenic acid (ALA), an omega-3 polyunsaturated fatty acid (PUFA). Activation of GPR120 in the intestines results in increased GLP-1 secretion from enteroendocrine L cells.

Question 3

You are testing a novel lipid molecule for its activity on vascular function in experimental animals. Your results demonstrate that the compound induces vasodilation by causing relaxation of smooth muscle. It also enhances platelet aggregation. These results indicate that your compound is most likely mimicking the effects of which of the following lipids?

A) docosahexaenoic acid, DHA
B) eicosapentaenoic acid, EPA
C) lysophosphatidic acid, LPA
D) lysophosphatidylinositol, LPI
E) oleoylethaolamide, OEA

lysophosphatidic acid, LPA

Accepted Answer

Lysophosphatidic acid (LPA) is known to cause vasodilation by relaxing smooth muscle and can also enhance platelet aggregation, similar to the effects observed with the novel lipid molecule. LPA, although being simple in structure, exerts a wide variety of cellular responses in many different cell types. LPA is known to enhance platelet aggregation, smooth muscle contraction, cell proliferation and migration, neurite retraction, and the secretion of chemokines and cytokines. The effects of LPA are the result of binding to at least 6 specific GPCRs (LPA₁-LPA₆).

Question 4

Lysophosphatidylinositol (LPI) has been shown to induce an increase in pancreatic insulin secretion. This effect is due to increasing intracellular calcium concentration. This effect of LPI is exerted by its binding to and activating which of the following receptors?

A) GPR35
B) GPR40
C) GPR41
D) GPR55
E) GPR120

Accepted Answer

LPI exerts its effect on pancreatic insulin secretion by binding to and activating GPR55, which leads to an increase in intracellular calcium concentration.  The primary receptor for LPI is GPR55 although additional studies have shown that LPI can also bind and activate GPR119. LPI activation of GPR55 results in increased intracellular calcium concentrations. This effect of LPI is associated with increased insulin release from the pancreas, arterial contraction, and the proliferation and migration of several cell type. In addition, LPI induces calcium flux in hepatic mitochondria. The effects of LPI on intracellular calcium mobilization are blocked by GPR55 antagonists as well as in cells where GPR55 levels have been downregulated demonstrating the specificity of the role of GPR55 in LPI action.

Question 5

You are testing a novel fatty acid-related compound for it efficacy in the treatment of obesity. When the compound is added to the chow of laboratory animals, there is a significant reduction in food intake leading to a reduction on overall body weight. You discover that the compound can bind to and activate the G-protein-coupled receptor, GPR119. Your results indicate that your test compound most likely functions similarly to which of the following lipids?

A) docosahexaenoic acid, DHA
B) eicosapentaenoic acid, EPA
C) lysophosphatidic acid, LPA
D) lysophosphatidylinositol, LPI
E) oleoylethaolamide, OEA

Accepted Answer

Oleoylethanolamide (OEA) is known to activate GPR119, leading to reduced food intake and weight loss, similar to the effects observed with the novel compound.  Oleoylethanolamide (OEA) is produced by mucosal cells in the proximal small intestine from dietary oleic acid. OEA has been shown to activate the fatty acid-sensing GPCR identified as GPR119. When OEA is administered to laboratory animals, the result is a significant reduction in food intake and body weight gain. These effects of OEA are the result of the activation of the nuclear receptor PPARα resulting in the observed modification of feeding behavior and motor activity in laboratory animals.

Question 6

Activation of which of the following receptors would be expected to be associated with increased glucose uptake by adipocytes?&#10;A) GPR35&#10;B) GPR40&#10;C) GPR55&#10;D) GPR119&#10;E) GPR120

Accepted Answer

GPR120 is highly expressed in adipose tissue and pro-inflammatory macrophages. DHA stimulation of GPR120 in adipocytes results in increased GLUT4 translocation to the cell surface with a subsequent increase in glucose transport into the cells.

Question 7

You are testing a novel compound related to the polyunsaturated fatty acid, DHA, for its effects on the activity of macrophages in culture. Addition of this compound to your cultures results in a significant reduction in the release to the media of tumor necrosis factor-α (TNF-α). Given these observation, your test compound is most likely binding to, and activating, which of the following receptors?

A) GPR35
B) GPR40
C) GPR41
D) GPR55
E) GPR120

Accepted Answer

GPR120 is known to be activated by omega-3 fatty acids like DHA and can mediate anti-inflammatory effects, such as reducing TNF-α release from macrophages.  The omega-3 PUFAs, DHA and EPA, exert potent anti-inflammatory effects through GPR120. It has been found that GPR120 functions as an omega-3 fatty acid receptor/sensor in pro-inflammatory macrophages and mature adipocytes. By signaling through GPR120, both DHAand EPA mediate potent anti-inflammatory effects. These effects are exerted by inhibition of the Toll-like receptor (TLR) and tumor necrosis factor-α (TNF-α) pro-inflammatory signaling pathways.

Deck 23: Lipids: Bioactive Lipids and Lipid-Sensing Receptors