Passage The sirtuins are a class of enzymes that regulate various metabolic processes by removing post-translational modifications from enzymes. SIRT4 is an autosomally encoded sirtuin protein that colocalizes with the pyruvate dehydrogenase complex. It deacylates lysine residues on certain metabolic proteins by removing methylglutaryl and hydroxymethylglutaryl units. Methylglutaryl-CoA and hydroxymethylglutaryl-CoA are intermediates in leucine catabolism, and scientists hypothesized that SIRT4 regulates this pathway. To test their hypothesis, livers from wild-type (WT) and SIRT4 knockout (KO) mice were treated with α-keto acid derivatives of several amino acids, including the derivative of leucine, α-ketoisocaproate (αKIC). Figures 1 and 2 show the rate of oxidation of α-keto acids and oxygen consumption in both WT and KO livers, respectively. Figure 1 Box plot showing the rate of oxidation of α-ketoisocaproate (αKIC), α-ketoglutarate (αKG), and pyruvate in SIRT4 knockout livers (Note: Asterisk indicates p

Question

Passage
The sirtuins are a class of enzymes that regulate various metabolic processes by removing post-translational modifications from enzymes. SIRT4 is an autosomally encoded sirtuin protein that colocalizes with the pyruvate dehydrogenase complex. It deacylates lysine residues on certain metabolic proteins by removing methylglutaryl and hydroxymethylglutaryl units. Methylglutaryl-CoA and hydroxymethylglutaryl-CoA are intermediates in leucine catabolism, and scientists hypothesized that SIRT4 regulates this pathway. To test their hypothesis, livers from wild-type (WT) and SIRT4 knockout (KO) mice were treated with α-keto acid derivatives of several amino acids, including the derivative of leucine, α-ketoisocaproate (αKIC) . Figures 1 and 2 show the rate of oxidation of α-keto acids and oxygen consumption in both WT and KO livers, respectively.

Figure 1 Box plot showing the rate of oxidation of α-ketoisocaproate (αKIC) , α-ketoglutarate (αKG) , and pyruvate in SIRT4 knockout livers (Note: Asterisk indicates p < 0.05 relative to WT level)

Figure 2 Oxygen consumption in WT and KO livers in the presence and absence of succinate and reduced cytochrome C (Cyt-C) Because leucine is known to regulate insulin secretion, scientists injected WT and KO mice with leucine and measured plasma insulin levels over time. They then injected mice with insulin and monitored blood glucose levels (Figure 3) .

Figure 3 (A) Plasma insulin levels after injection with leucine and (B) blood glucose levels after injection with insulin in both WT and KO mice
Adapted from Anderson KA, Huynh FK, Fisher-Wellman K, et al. SIRT4 Is a Lysine Deacylase that Controls Leucine Metabolism and Insulin Secretion. Cell Metab. 2017;25(4) :838-855.e15.
-Which conclusion about the effect of SIRT4 on blood glucose levels can be drawn from the data in Figure 3?

Quizplus · Accepted Answer

11ecba2d_0ec0_bef8_a3bf_c536658401de_MD0008_00 Metabolic signals such as high glucose or high leucine levels promote insulin secretion by the pancreas. Insulin then induces glucose uptake by cells, leading to a decrease in blood glucose levels. However, cells that are overexposed to insulin can become resistant and take up less glucose even when insulin is present. Part A of Figure 3 shows that KO mice have elevated insulin levels relative to WT mice even before insulin secretion is induced by leucine injection. When leucine is injected, plasma insulin rises more in KO mice than in WT mice and takes longer to return to its baseline level. Part B of the figure shows that in WT mice, blood glucose is significantly decreased when insulin is injected. In contrast, blood glucose in KO mice remains at or above 100% of its baseline level for several minutes after insulin injection and then decreases slowly, indicating insulin resistance. Therefore, SIRT4 (present only in WT mice) prevents the development of insulin resistance and facilitates glucose uptake. (Choice A) Figure 3 shows that WT mice produce less insulin than KO mice, so SIRT4 (present only in WT mice) most likely downregulates insulin secretion. In addition, insulin secretion would cause increased glucose uptake. (Choice C) Increased insulin sensitivity would result in increased glucose uptake, which would lead to decreased blood glucose. (Choice D) Insulin induces glucose uptake, so the decreased insulin secretion in the presence of SIRT4 (only present in WT mice) is not likely to increase glucose uptake. Instead, the absence of excess insulin likely prevents insulin resistance from developing and allows for more glucose uptake in spite of the lower insulin levels present in WT mice. Educational objective: Insulin is secreted in response to metabolic signals such as high blood glucose and induces glucose uptake by cells. Cells that are overexposed to insulin can develop resistance and take up less glucose than they normally would in the presence of insulin.

Passage The Sirtuins Are a Class of Enzymes That Regulate Various