Intestinal HIF-2α Regulates GLP-1 Secretion via Lipid Sensing in L-Cells

Mooli, Raja Gopal Reddy; Mukhi, Dhanunjay; Pasupulati, Anil Kumar; Evers, Simon S.; Sipula, Ian; Jurczak, Michael J.; Seeley, Randy J.; Shah, Yatrik M.; Ramakrishnan, S

doi:10.1016/j.jcmgh.2021.12.004

Cited by 9 publications

(6 citation statements)

References 60 publications

(82 reference statements)

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“…At week 4, we performed intraperitoneal glucose tolerance test (GTT) and insulin tolerance test (ITT) in mice respectively, according to the methods described by Le, J 35 and Mooli. 36 Mice were placed in clean cages and fasted with free access to water. For the GTT, mice were fasted for 12 h and baseline blood glucose was measured using a glucometer.…”

Section: Methodsmentioning

confidence: 99%

Vancomycin relieves tacrolimus-induced hyperglycemia by eliminating gut bacterial beta-glucuronidase enzyme activity

Li,

Zhang,

Zhou

et al. 2024

Gut Microbes

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Up to 40% of transplant recipients treated long-term with tacrolimus (TAC) develop post-transplant diabetes mellitus (PTDM). TAC is an important risk factor for PTDM, but is also essential for immunosuppression after transplantation. Long-term TAC treatment alters the gut microbiome, but the mechanisms of TAC-induced gut microbiota in the pathogenesis of PTDM are poorly characterized. Here, we showed that vancomycin, an inhibitor of bacterial beta-glucuronidase (GUS), prevents TAC-induced glucose disorder and insulin resistance in mice. Metagenomics shows that GUS-producing bacteria are predominant and flourish in the TAC-induced hyperglycemia mouse model, with upregulation of intestinal GUS activity. Targeted metabolomics analysis revealed that in the presence of high GUS activity, the hydrolysis of bile acid (BAs)-glucuronic conjugates is increased and most BAs are overproduced in the serum and liver, which, in turn, activates the ileal farnesoid X receptor (FXR) and suppresses GLP-1 secretion by L-cells. The GUS inhibitor vancomycin significantly eliminated GUS-producing bacteria and inhibited bacterial GUS activity and BAs levels, thereby enhancing L-cell GLP-1 secretion and preventing hyperglycemia. Our results propose a novel clinical strategy for inhibiting the bacterial GUS enzyme to prevent hyperglycemia without requiring withdrawal of TAC treatment. This strategy exerted its effect through the ileal bile acid-FXR-GLP-1 pathway.

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Section: Methodsmentioning

confidence: 99%

Vancomycin relieves tacrolimus-induced hyperglycemia by eliminating gut bacterial beta-glucuronidase enzyme activity

Li,

Zhang,

Zhou

et al. 2024

Gut Microbes

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“…Cells or human and mouse frozen tissues (~10mg) were homogenized using radioimmunoprecipitation assay lysis buffer (0.5% NP-40, 0.1% sodium deoxycholate, 150 mmol/L NaCl, 50 mmol/L Tris-Cl, pH 7.5) containing 1 mmol/L phenylmethylsulphonyl fluoride, protease inhibitor cocktail (Sigma-Aldrich) and 2 mmol/L sodium orthovanadate 24 . The homogenate was centrifuged at 13,000 × g for 10 min at 4°C to collect the supernatant.…”

Section: Methodsmentioning

confidence: 99%

Hepatic ketogenesis regulates lipid homeostasis via ACSL1-mediated fatty acid partitioning

Ramakrishnan,

Mooli,

Han

et al. 2023

Preprint

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Liver-derived ketone bodies play a crucial role in fasting energy homeostasis by fueling the brain and peripheral tissues. Ketogenesis also acts as a conduit to remove excess acetyl-CoA generated from fatty acid oxidation and protects against diet-induced hepatic steatosis. Surprisingly, no study has examined the role of ketogenesis in fasting-associated hepatocellular lipid metabolism. Ketogenesis is driven by the rate-limiting mitochondrial enzyme 3-hydroxymethylglutaryl CoA synthase (HMGCS2) abundantly expressed in the liver. Here, we show that ketogenic insufficiency via disruption of hepatic HMGCS2 exacerbates liver steatosis in fasted chow and high-fat-fed mice. We found that the hepatic steatosis is driven by increased fatty acid partitioning to the endoplasmic reticulum (ER) for re-esterification via acyl-CoA synthetase long-chain family member 1 (ACSL1). Mechanistically, acetyl-CoA accumulation from impaired hepatic ketogenesis is responsible for the elevated translocation of ACSL1 to the ER. Moreover, we show increased ER-localized ACSL1 and re-esterification of lipids in human NASH displaying impaired hepatic ketogenesis. Finally, we show that L-carnitine, which buffers excess acetyl-CoA, decreases the ER-associated ACSL1 and alleviates hepatic steatosis. Thus, ketogenesis via controlling hepatocellular acetyl-CoA homeostasis regulates lipid partitioning and protects against hepatic steatosis.

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“…The authors showed that activation of intestinal HIF2α during obesity increased ceramide synthesis fueling hepatic steatosis. However, Mooli et al (81) reported that intestinal HIF2α regulated lipid sensing and increased GLP-1 secretion, thereby protecting against diet-induced obesity and hepatic steatosis. These contradictory findings suggest a complex role for intestinal HIF2α influencing hepatic steatosis, which may further be attributed to activation of HIF2α in a specific intestinal cell type, enterocytes, compared with enteroendocrine L cells.…”

Section: Intersection Of Gut/liver Hif Axis In Ibd and Fldmentioning

confidence: 99%

Hypoxia-Induced Signaling in Gut and Liver Pathobiology

Solanki,

Shah

2024

Annu. Rev. Pathol. Mech. Dis.

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Oxygen (O2) is essential for cellular metabolism and biochemical reactions. When the demand for O2 exceeds the supply, hypoxia occurs. Hypoxia-inducible factors (HIFs) are essential to activate adaptive and survival responses following hypoxic stress. In the gut (intestines) and liver, oxygen gradients or physiologic hypoxia are necessary to maintain normal homeostasis. While physiologic hypoxia is beneficial and aids in normal functions, pathological hypoxia is harmful as it exacerbates inflammatory responses and tissue dysfunction and is a hallmark of many cancers. In this review, we discuss the role of gut and liver hypoxia-induced signaling, primarily focusing on HIFs, in the physiology and pathobiology of gut and liver diseases. Additionally, we examine the function of HIFs in various cell types during gut and liver diseases, beyond intestinal epithelial and hepatocyte HIFs. This review highlights the importance of understanding hypoxia-induced signaling in the pathogenesis of gut and liver diseases and emphasizes the potential of HIFs as therapeutic targets. Expected final online publication date for the Annual Review of Pathology: Mechanisms of Disease, Volume 19 is January 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

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Intestinal HIF-2α Regulates GLP-1 Secretion via Lipid Sensing in L-Cells

Cited by 9 publications

References 60 publications

Vancomycin relieves tacrolimus-induced hyperglycemia by eliminating gut bacterial beta-glucuronidase enzyme activity

Vancomycin relieves tacrolimus-induced hyperglycemia by eliminating gut bacterial beta-glucuronidase enzyme activity

Hepatic ketogenesis regulates lipid homeostasis via ACSL1-mediated fatty acid partitioning

Hypoxia-Induced Signaling in Gut and Liver Pathobiology

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