Canagliflozin Facilitates Reverse Cholesterol Transport Through Activation of AMPK/ABC Transporter Pathway

Zhao, Yingnan; Li, Yanping; Liu, Qinhui; Tang, Qin; Zhang, Zijing; Zhang, Jinhang; Huang, Cuiyuan; Huang, Hui; Zhang, Guorong; Zhou, Jian; Yan, Jiamin; Xia, Yan; Zhang, Zhiyong; He, Jinhan

doi:10.2147/dddt.s306367

Cited by 10 publications

(8 citation statements)

References 43 publications

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“…Members of ECIR were using SGLT2 inhibitors for 2 years before the first case of hypertriglyceridemia was incidentally noted. Hypertriglyceridemia was not an expected side effect from the review of the response of humans to this class of drugs ( Euh et al , 2021 ; Li et al , 2021 ; Luo et al , 2021 ; Zhao et al , 2021 ; Chen et al , 2022 ; Lee et al , 2022 ). However, the human diet even with diabetes is considerably higher in simple sugar and starch (35+%) ( Gray and Threlkeld, 2019 ) than the equine on restricted metabolic syndrome diets (less than 10%).…”

Section: Discussionmentioning

confidence: 99%

“…SGLT2 inhibitors in humans and experimental animals have not been linked to worsening of the lipid profile. In fact, improvement has been reported in fatty liver parameters as well as blood levels and liver enzymes ( Euh et al , 2021 ; Li et al , 2021 ; Luo et al , 2021 ; Zhao et al , 2021 ; Chen et al , 2022 ; Lee et al , 2022 ). When details of the index case were reported, we notified veterinarians overseeing horses on SGLT2 inhibitors and suggested adding triglycerides to pretreatment screening and posttreatment monitoring.…”

Section: Introductionmentioning

confidence: 98%

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Hypertriglyceridemia in equines with refractory hyperinsulinemia treated with SGLT2 inhibitors

Kellon¹,

Gustafson²

2023

Open Vet J

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Background: Sodium-Glucose CoTransporter-2 [SGLT2] inhibitors, the -flozin group of drugs, which block glucose reuptake in the renal proximal tubule, are being increasingly used off-label to treat horses with refractory hyperinsulinemia. After two years of use by animals in our group, a horse on canagliflozin was incidentally noted to be hyperlipemic. Case Description: We have been following a cohort of equines (n=20) treated with SGLT2 inhibitors due to refractory hyperinsulinemia. The animals are owned by members of the Equine Cushing’s and Insulin Resistance Group (ECIR) and treated by their attending veterinarians. The index case was a 23 year old gelding with a 2 year history of recurring laminitis that began canagliflozin therapy to control hyperinsulinemia which was no longer responsive to metformin. Between 6-10 weeks post therapy, significant weight loss was noticed. Two days later he was hospitalized with colic symptoms and hyperlipemia but was bright, alert and eating well throughout. Canagliflozin was discontinued and triglycerides returned to normal reference values within 10 days. Subsequent study of 19 other horses on SGLT2 inhibitors revealed varying degrees of hypertriglyceridemia, all asymptomatic. Conclusion: While this class of drugs holds great promise for cases of refractory hyperinsulinemia and laminitis that do not respond to diet or metformin therapy, hypertriglyceridemia is a potential side effect. In our experience, animals remained asymptomatic and eating well. Further study of hypertriglyceridemia in horses on SGLT2 inhibitors and the possible mitigating effect of diet is indicated. To our knowledge, this is the first published report of hypertriglyceridemia with SGLT2 inhibitor treatment in equines.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

Hypertriglyceridemia in equines with refractory hyperinsulinemia treated with SGLT2 inhibitors

Kellon¹,

Gustafson²

2023

Open Vet J

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“…Moreover, treatment of HepG2 cells with canagliflozin facilitated hepatic cholesterol efflux via activation of AMPK. In turn, AMPK activation led to increased expression of the liver X receptor (LXR) and its downstream proteins, resulting in subsequent stimulation of cholesterol reverse transport [ 91 ]. LXR activation also accelerates fecal cholesterol disposal through regulation of ATP-binding cassette (ABC) transporters ABCG5 and ABCG8 expression [ 92 ].…”

Section: Sglt-2 Inhibitors In Nafldmentioning

confidence: 99%

“…LXR activation also accelerates fecal cholesterol disposal through regulation of ATP-binding cassette (ABC) transporters ABCG5 and ABCG8 expression [ 92 ]. Canagliflozin treatment resulted in reduced expressions of ABCG5 and ABCG8 and LXR, while this effect was inhibited after treatment of cells with compound C [ 91 ]. An increased AMP/ADP ratio leads to AMPK activation.…”

Section: Sglt-2 Inhibitors In Nafldmentioning

confidence: 99%

SGLT-2 Inhibitors in NAFLD: Expanding Their Role beyond Diabetes and Cardioprotection

Ανδρουτσάκος

Nasiri-Ansari

Bakasis

et al. 2022

IJMS

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Non-alcoholic fatty liver disease (NAFLD) is an ‘umbrella’ term, comprising a spectrum ranging from benign, liver steatosis to non-alcoholic steatohepatitis, liver fibrosis and eventually cirrhosis and hepatocellular carcinoma. NAFLD has evolved as a major health problem in recent years. Discovering ways to prevent or delay the progression of NAFLD has become a global focus. Lifestyle modifications remain the cornerstone of NAFLD treatment, even though various pharmaceutical interventions are currently under clinical trial. Among them, sodium-glucose co-transporter type-2 inhibitors (SGLT-2i) are emerging as promising agents. Processes regulated by SGLT-2i, such as endoplasmic reticulum (ER) and oxidative stress, low-grade inflammation, autophagy and apoptosis are all implicated in NAFLD pathogenesis. In this review, we summarize the current understanding of the NAFLD pathophysiology, and specifically focus on the potential impact of SGLT-2i in NAFLD development and progression, providing current evidence from in vitro, animal and human studies. Given this evidence, further mechanistic studies would advance our understanding of the exact mechanisms underlying the pathogenesis of NAFLD and the potential beneficial actions of SGLT-2i in the context of NAFLD treatment.

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“… 11 , 12 Another study has demonstrated that canagliflozin can regulate cholesterol metabolism and improve blood lipids. 13 Moreover, Shib et al 14 have demonstrated that canagliflozin relieves the symptoms of or even delays the onsets of NASH and HCC. However, how canagliflozin alleviates the developments of hepatic steatosis and atherosclerosis has not yet been fully understood.…”

Section: Introductionmentioning

confidence: 99%

Canagliflozin Attenuates Hepatic Steatosis and Atherosclerosis Progression in Western Diet-Fed ApoE-Knockout Mice

Zuo¹,

Zhang²,

He³

et al. 2022

DDDT

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Purpose To investigate the effect of canagliflozin (20 mg/kg) on hepatic steatosis and atherosclerosis, and further to explore its possible mechanism. Methods Blood glucose, blood lipid, oxidative stress response and inflammatory cytokines were examined by intraperitoneal glucose tolerance test and ELISA assay. HE and Oil Red O staining were used to estimate the extent of hepatic steatosis and atherosclerosis. RNA-seq and qRT-PCR were used to further investigate the potential mechanism. The effects of canagliflozin on autophagy were detected using transmission electron microscopy and Western blotting. The endothelial function-related markers were determined by qRT-PCR. Results Canagliflozin notably alleviated the elevation in blood glucose and insulin resistance in western diet-fed ApoE-/- mice. In ApoE-/-+Cana group, ApoE-/- mice had lower levels of TG, TC, LDL-C, TNF-α, IL-6, IL-1β, and MCP-1. HE and Oil Red O staining presented that canagliflozin restrained the atherosclerotic plaque development and lipid accumulation. RNA-seq showed that 87 DEGs were relevant to improvement of hepatic steatosis and atherosclerosis by canagliflozin. Among them, CPS1, ASS1, ASL, ARG1, MATLA, GLS2, GOT1, SREBP1, Plin5, Retreg1, and C/EBPβ were verified. KEGG enrichment analysis indicated that DEGs were mainly involved in amino acid metabolism. Besides, we observed that canagliflozin reduced the contents of aspartic acid and citrulline in liver. Western blotting showed that ASS1 and p-AMPK/AMPK was remarkably elevated after administration of canagliflozin. Correspondingly, canagliflozin down-regulated SREBP1, FAS, ACC1, HMGCR, p-mTOR/m-TOR, p-ULK1/ULK1 and p62, but up-regulated CPT1, Beclin 1 and LC3 II/LC3I. TEM showed that canagliflozin reduced the number of lipid droplets and increased the autophagosomes. Moreover, we found that canagliflozin elevated the aortic endothelial function-associated markers including ASS1, ASL and eNOS. Conclusion Canagliflozin may attenuate hepatic steatosis by improving lipid metabolism, enhancing autophagy, and reducing inflammatory response through ASS1/AMPK pathway. Besides, canagliflozin further effectively improves the aortic endothelial function, thereby suppressing atherosclerosis development.

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Canagliflozin Facilitates Reverse Cholesterol Transport Through Activation of AMPK/ABC Transporter Pathway

Cited by 10 publications

References 43 publications

Hypertriglyceridemia in equines with refractory hyperinsulinemia treated with SGLT2 inhibitors

Hypertriglyceridemia in equines with refractory hyperinsulinemia treated with SGLT2 inhibitors

SGLT-2 Inhibitors in NAFLD: Expanding Their Role beyond Diabetes and Cardioprotection

Canagliflozin Attenuates Hepatic Steatosis and Atherosclerosis Progression in Western Diet-Fed ApoE-Knockout Mice

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