Dipeptidyl Peptidase-4 Inhibition in Non-Alcoholic Fatty Liver Disease

Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum of hepatic disorders characterised by excessive lipid accumulation in hepatocytes in the absence of significant alcohol intake. Progression to non-alcoholic steatohepatitis (NASH) involves inflammation, hepatocellular injury and varying degrees of fibrosis, ultimately elevating the risk of cirrhosis and hepatocellular carcinoma. Dipeptidyl peptidase-4 (DPP4) is a serine protease abundant in the liver and circulation, which inactivates incretin hormones such as glucagon-like peptide-1. Pharmacological inhibition of DPP4, originally developed for type 2 diabetes, has emerged as a potential strategy to ameliorate hepatic steatosis, inflammation and fibrogenesis. Preclinical studies reveal that DPP4 inhibitors modulate immune cell activation, suppress pro-inflammatory cytokine release, induce autophagy and attenuate lipoapoptosis, offering benefits that extend beyond glycaemic control. Clinical observations and biomarker analyses indicate that elevated circulating DPP4 activity correlates with disease severity in NAFLD, suggesting both mechanistic insight and potential for risk stratification. The collective evidence underscores the global significance of repurposing DPP4 inhibitors to address the growing burden of fatty liver disease through multifaceted mechanisms.

Research from Nature Portfolio

In a murine model of genetically induced obesity and insulin resistance, long-term administration of a DPP4 inhibitor prevented the transition from simple steatosis to NASH and subsequent tumour development. These effects occurred independently of weight loss or systemic metabolic changes and were linked to suppression of liver macrophage activation via enhanced glucagon-like peptide-1 signalling, leading to reduced expression of pro-inflammatory and pro-fibrotic mediators.

Another study employing a high-fat, high-fructose diet to induce NASH in mice demonstrated that treatment with a distinct DPP4 inhibitor significantly improved hepatic steatosis and fibrosis. The therapeutic benefit was attributed to attenuation of TRAIL receptor-mediated hepatocyte apoptosis and downregulation of hepatic DPP4 expression, highlighting a liver-specific mechanism of action that mitigates lipotoxicity and tissue remodelling.

Dipeptidyl Peptidase-4 Inhibition in Non-Alcoholic Fatty Liver Disease publication trend

The graph below shows the total number of articles in dipeptidyl peptidase-4 inhibition in non-alcoholic fatty liver disease across all publications each year (not limited to Nature Index journals).

Technical terms

Dipeptidyl peptidase-4 (DPP4): A serine protease that cleaves and inactivates incretin hormones, expressed on cell surfaces and in circulation.

Non-alcoholic fatty liver disease (NAFLD): A spectrum of liver conditions characterised by hepatocellular fat accumulation unrelated to alcohol consumption.

Non-alcoholic steatohepatitis (NASH): A progressive form of NAFLD marked by inflammation, hepatocyte injury and variable fibrosis.

Incretin hormones: Gastrointestinal peptides, notably glucagon-like peptide-1, that enhance insulin secretion in response to nutrient intake.

Autophagy: A conserved cellular process for degrading and recycling cytoplasmic constituents, instrumental in lipid clearance and organelle quality control.

Fibrosis: The excessive deposition of extracellular matrix proteins in the liver, leading to architectural distortion and potential progression to cirrhosis.

References

1. Gemigliptin, a DPP4 inhibitor, ameliorates nonalcoholic steatohepatitis through AMP-activated protein kinase-independent and ULK1-mediated autophagy. Molecular Metabolism (2023).
2. Comparison of efficacy of anti-diabetics on non-diabetic NAFLD: A network meta-analysis. Frontiers in Pharmacology (2023).
3. Dipeptidyl peptidase-4 inhibition prevents nonalcoholic steatohepatitis–associated liver fibrosis and tumor development in mice independently of its anti-diabetic effects. Scientific Reports (2020).
4. Circulating dipeptidyl peptidase-4 is independently associated with the presence and severity of NAFLD/NASH in individuals with and without obesity and metabolic disease. Journal of Endocrinological Investigation (2020).
5. Effects of sitagliptin on intrahepatic lipid content in patients with non-alcoholic fatty liver disease. Frontiers in Endocrinology (2022).
6. Dipeptidyl peptidase-4 inhibitor protects against non-alcoholic steatohepatitis in mice by targeting TRAIL receptor-mediated lipoapoptosis via modulating hepatic dipeptidyl peptidase-4 expression. Scientific Reports (2020).