The Role of Sirt6 in Obesity and Diabetes

Parietal cells of the gastric mucosa contain a complex and extensive secretory membrane system that harbors gastric H+, K+-adenosine triphosphatase (ATPase), the enzyme primarily responsible for gastric lumen acidification. Here, we describe the characterization of mice deficient in the H+, K+-ATPase α subunit (Atp4a−/−) to determine the role of this protein in the biosynthesis of this membrane system and the biology of the gastric mucosa. Atp4a−/− mice were produced by gene targeting. Wild-type (WT) and Atp4a−/− mice, paired for age, were examined at 10, 12, 14 and 16 weeks for histopathology, and the expression of mucin 2 (MUC2), α-methylacyl-CoA racemase (AMACR), Ki-67 and p53 proteins was analyzed by immunohistochemistry. For further information, phosphoinositide 3-kinase (PI3K), phosphorylated-protein kinase B (p-AKT), mechanistic target of rapamycin (mTOR), hypoxia-inducible factor 1α (HIF-1α), lactate dehydrogenase A (LDHA) and sirtuin 6 (SIRT6) were detected by Western blotting. Compared with the WT mice, hypochlorhydric Atp4a−/− mice developed parietal cell atrophy and significant antral inflammation (lymphocyte infiltration) and intestinal metaplasia (IM) with elevated MUC2 expression. Areas of dysplasia in the Atp4a−/− mouse stomach showed increased AMACR and Ki-67 expression. Consistent with elevated antral proliferation, tissue isolated from Atp4a−/− mice showed elevated p53 expression. Next, we examined the mechanism by which the deficiency of the H+, K+-ATPase α subunit has an effect on the gastric mucosa. We found that the expression of phosphorylated-PI3K, p-AKT, phosphorylated-mTOR, HIF-1α, LDHA and SIRT6 was significantly higher in tissue from the Atp4a−/− mice compared with the WT mice (P<0.05). The H+, K+-ATPase α subunit is required for acid-secretory activity of parietal cells in vivo, the normal development and cellular homeostasis of the gastric mucosa, and attainment of the normal structure of the secretory membranes. Chronic achlorhydria and hypergastrinemia in aged Atp4a−/− mice produced progressive hyperplasia and mucolytic and IM, and activated the Warburg effect via PI3K/AKT/mTOR signaling.

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“…SIRT6 plays an important role in glucose production and metabolism [46]. SIRT6 affects both gluconeogenesis and glycolysis [47,48].…”

Section: Discussionmentioning

confidence: 99%

Dynamic characterization of intestinal metaplasia in the gastric corpus mucosa of Atp4a-deficient mice

Liu

Yuan

et al. 2020

Bioscience Reports

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“…Previous studies demonstrated that Sirt6 functions as a transcriptional repressor by deacetylating the histones H3K9 and H3K56 on the promoters of multiple genes (41). Sirt6 also deacetylated nonhistone proteins such as general control nonrepressed protein 5 and forkhead box O1 and O3 (14).…”

Section: Sirt6 Regulates Ketogenesismentioning

confidence: 99%

Hepatocyte-specific Sirt6 deficiency impairs ketogenesis

Chen

Liu

Tang

et al. 2019

Journal of Biological Chemistry

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Sirt6 is an NADH (NAD ؉ )-dependent deacetylase with a critical role in hepatic lipid metabolism. Ketogenesis is controlled by a signaling network of hepatic lipid metabolism. However, how Sirt6 functions in ketogenesis remains unclear. Here, we demonstrated that Sirt6 functions as a mediator of ketogenesis in response to a fasting and ketogenic diet (KD). The KD-fed hepatocyte-specific Sirt6 deficiency (HKO) mice exhibited impaired ketogenesis, which was due to enhanced Fsp27 (fatspecific induction of protein 27), a protein known to regulate lipid metabolism. In contrast, overexpression of Sirt6 in mouse primary hepatocytes promoted ketogenesis. Mechanistically, Sirt6 repressed Fsp27␤ expression by interacting with Crebh (cAMP response element-binding protein H) and preventing its recruitment to the Fsp27␤ gene promoter. The KD-fed HKO mice also showed exacerbated hepatic steatosis and inflammation. Finally, Fsp27 silencing rescued hypoketonemia and other metabolic phenotypes in KD-fed HKO mice. Our data suggest that the Sirt6 -Crebh-Fsp27 axis is pivotal for hepatic lipid metabolism and inflammation. Sirt6 may be a pharmacological target to remedy metabolic diseases. De novo lipogenesis analysis using stable isotopes tracerNewly isolated mouse primary hepatocytes were seeded in 10-cm culture dishes and cultured in low-glucose Dulbecco's Sirt6 regulates ketogenesis

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“…SIRT2 has been linked with regulation of the activity of some Ras proteins via control of the deacylation of an internal lysine side chain . It is notable that some sirtuins, such as SIRT6, are associated with disorders in lipid and fat metabolism such as steatosis …”

Section: Is Reversal Of Intrinsic Lipidation Mediated By Deacylases Amentioning

confidence: 99%

“…[26,27] It is notable that some sirtuins, such as SIRT6, are associated with disorders in lipid and fat metabolism such as steatosis. [28] With the increasing availability of simultaneous inhibitors for multiple classes of sirtuin (pan-inhibitors), [18,29,30] it should be possible to probe the hypothesis that they are involved in reversing lysine modification by intrinsic lipidation by examining the downstream effects of sirtuin inhibition on the accumulation of proteins modified at internal lysines. This would complement experiments where reduced sirtuin activity has been shown to lead to hyperacetylation of histone proteins.…”

Section: Is Reversal Of Intrinsic Lipidation Mediated By Deacylases Amentioning

confidence: 99%

Far from Inert: Membrane Lipids Possess Intrinsic Reactivity That Has Consequences for Cell Biology

Sanderson

2020

BioEssays

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In this article, it is hypothesized that a fundamental chemical reactivity exists between some non‐lipid constituents of cellular membranes and ester‐based lipids, the significance of which is not generally recognized. Many peptides and smaller organic molecules have now been shown to undergo lipidation reactions in model membranes in circumstances where direct reaction with the lipid is the only viable route for acyl transfer. Crucially, drugs like propranolol are lipidated in vivo with product profiles that are comparable to those produced in vitro. Some compounds have also been found to promote lipid hydrolysis. Drugs with high lytic activity in vivo tend to have higher toxicity in vitro. Deacylases and lipases are proposed as key enzymes that protect cells against the effects of intrinsic lipidation. The toxic effects of intrinsic lipidation are hypothesized to include a route by which nucleation can occur during the formation of amyloid fibrils.

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The Role of Sirt6 in Obesity and Diabetes

Cited by 99 publications

References 82 publications

Dynamic characterization of intestinal metaplasia in the gastric corpus mucosa of Atp4a-deficient mice

Dynamic characterization of intestinal metaplasia in the gastric corpus mucosa of Atp4a-deficient mice

Hepatocyte-specific Sirt6 deficiency impairs ketogenesis

Far from Inert: Membrane Lipids Possess Intrinsic Reactivity That Has Consequences for Cell Biology

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