Albumin-fused long-acting FGF21 analogue for the treatment of non-alcoholic fatty liver disease

Jan 23, 2023Journal of controlled release : official journal of the Controlled Release Society

Long-lasting FGF21 protein linked to albumin for treating non-alcoholic fatty liver disease

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Abstract

About 25% of the world's population is affected by non-alcoholic fatty liver disease (NAFLD).

HSA-FGF21 treatment reduced body weight and improved blood sugar and insulin levels in mice with NAFLD induced by a high-fat diet.
The therapy led to decreased levels of plasma and liver lipids, particularly certain fatty acids, in the treated mice.
HSA-FGF21 also suppressed the expression of receptors and enzymes associated with fat accumulation in the liver.
In adipose tissue, HSA-FGF21 improved fat cell size, reduced inflammation, and increased levels of beneficial proteins.
Treatment with HSA-FGF21 resulted in lower liver enzyme levels and reduced signs of oxidative stress and inflammation.

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Non-alcoholic fatty liver disease (NAFLD) currently affects about 25% of the world's population, and the numbers continue to rise as the number of obese patients increases. However, there are currently no approved treatments for NAFLD. This study reports on the evaluation of the therapeutic effect of a recombinant human serum albumin-fibroblast growth factor 21 analogue fusion protein (HSA-FGF21) on the pathology of NAFLD that was induced by using two high-fat diets (HFD), HFD-60 and STHD-01. The HFD-60-induced NAFLD model mice with obesity, insulin resistance, dyslipidemia and hepatic lipid accumulation were treated with HSA-FGF21 three times per week for 4 weeks starting at 12 weeks after the HFD-60 feeding. The administration of HSA-FGF21 suppressed the increased body weight, improved hyperglycemia, hyperinsulinemia, and showed a decreased accumulation of plasma lipid and hepatic lipid levels. The elevation of C16:0, C18:0 and C18:1 fatty acids in the liver that were observed in the HFD-60 group was recovered by the HSA-FGF21 administration. The increased expression levels of the hepatic fatty acid uptake receptor (CD36) and fatty acid synthase (SREBP-1c, FAS, SCD-1, Elovl6) were also suppressed. In adipose tissue, HSA-FGF21 caused an improved adipocyte hypertrophy, a decrease in the levels of inflammatory cytokines and induced the expression of adiponectin and thermogenic factors. The administration of HSA-FGF21 to the STHD-01-induced NAFLD model mice resulted in suppressed plasma ALT and AST levels, oxidative stress, inflammatory cell infiltration and fibrosis. Together, HSA-FGF21 has some potential for use as a therapeutic agent for the treatment of NAFLD.

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Albumin-fused long-acting FGF21 analogue for the treatment of non-alcoholic fatty liver disease

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