Canagliflozin and Hepatic Steatosis and Herosclerosis

Canagliflozin is a medicine that has shown some promise in treating people with hepatic steatosis and herosclerosis. This article provides a review of the medicine and some of the findings of research that has been carry out on it.


Canagliflozin is an FDA-approve medicine for treatment of type 2 diabetes. It is known to affect the metabolism of lipids and visceral fat depots. As a result, it may be beneficial for patients with nonalcoholic fatty liver disease (NAFLD).

Although NAFLD is a complex disease, researchers have been able to identify several key mechanisms involve. These include the production of toxic lipid species, hepatocyte dysfunction, and inflammation.

In NAFLD, steatosis is a major metabolic derangement that leads to the accumulation of excess free fatty acids. These fatty acids trigger the development of apoptosis in hepatocytes. However, how this disease progresses from steatosis to fibrosis is not well understood.

Study design

Nonalcoholic fatty liver disease (NAFLD) is a chronic liver disorder characterize by hepatic steatosis and inflammation. It can develop into hepatic fibrosis and eventually into cirrhosis.

NAFLD is the most common type of hepatic disease in the United States. The prevalence is as high as 80% in obese patients. However, NAFLD and hepatic fibrosis are associate with an increase risk for cardiovascular diseases and mortality. Currently, there are no approve medicines for NAFLD. Nonetheless, new medicines are under development and there are promising approaches to improve NAFLD management.

Canagliflozin is a sodium-glucose transporter 2 inhibitor (SGLT-2i) that inhibits glucose uptake, increases glucose excretion via urine, and inhibits hepatic proliferation of hepatocellular cell lines. In addition to being a promising agent for the treatment of NAFLD, SGLT-2i has been shown to impact atherosclerosis.

DEGs were enriche into top 20 pathways in KEGG enrichment analysis

Canagliflozin is show to have a protective effect against hepatic steatosis and herosclerosis. The effects of canagliflozin on the liver were assesse by evaluating the serum levels of cholesterol, glucose, and triglycerides. It also inhibite the development of atherosclerotic plaques. In ApoE-/- mice, canagliflozin reduce inflammation and insulin resistance while improving blood lipid profiles.

To better understand the potential of canagliflozin in improving hepatic steatosis, we analyze the effect of canagliflozin on hepatic gene expression using RNA-seq. We found that canagliflozin significantly restored the levels of Plin5, C/EBPb, and triglyceride in the ApoE-/- group. This was accompaniedby a reduction in the amount of total cholesterol and low-density lipoprotein cholesterol in the same group.

DEGs were decrease starch and galactose metabolism

Canagliflozin is show to be effective in decreasing the starch and galactose metabolism in hepatic steatosis and herosclerosis in an atherosclerotic mouse model. The SGLT2i agent can also inhibit de novo lipogenesis, attenuate oxidative stress and inflammatory cytokines, and decrease hepatic macrophage content. Its anti-atherosclerosis activity is associate with activation of AMPK.

This study aims to determine whether canagliflozin can have an effect on the atherogenesis process in an atherosclerotic mouse xenograft model. To this end, the authors use western blot assay and qRT-PCR to examine the mRNA levels of various genes in the liver of ApoE-/- mice.

Several genes were identifie as being up-regulate in the ApoE-/- group. The expression of Plin5, VCAM-1, ASL, C/EBPb, ACC1, SREBP1, FAS and p-ULK1/ULK1 were found to be increase. On the other hand, the expression of MCP-1, LC3I/LC3I, p-mTOR and HMGCR was decrease.

NLRP3 inflammasome inhibition

Canagliflozin is an FDA approve treatment for type 2 diabetes. It also decreases visceral fat depots and body fat mass. In vitro studies have shown that canagliflozin inhibits NLRP3/caspase-1/GSDMD inflammasomes in pancreatic b cells. However, the specific mechanism is not well understood.

In NAFLD, excess free fatty acids cause apoptosis of cardiomyocytes and endothelial cells, leading to the generation of toxic metabolites. The formation of hepatic steatosis can lead to oxidative stress, which in turn, may induce atherosclerosis.

Scientists have identify multiple pathophysiological processes involve in the development of NAFLD, including dysregulation of lipid metabolism, increase hepatic inflammation, and genetic predisposition. The presence of a variant of the PNPLA3 gene has been linke to the increase susceptibility to NAFLD.

DEGs were decrease cholesterol synthesis

Canagliflozin is a new drug use in type 2 diabetes mellitus that is believe to treat both atherosclerosis and nonalcoholic fatty liver disease (NAFLD). This medicine is reduce liver fat accumulation, reduce hyperlipidemia, and improve endothelial function. In this study, we examine the effects of canagliflozin on hepatic steatosis and herosclerosis in western diet fed ApoE-/- mice. RNA-sequencing was use to identify the genes that were differentially expresse.

We found that canagliflozin significantly reduce the inflammatory response, lipid deposition, and the atherogenesis process. Moreover, it induce autophagy in ApoE-/- mice. It also reduce atherogenesis plaque area. This may be due to canagliflozin’s inhibition of fatty acid oxidation and activation of AMPK.

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