Ahnak deficiency attenuates high-fat diet-induced fatty liver in mice through FGF21 induction

• Published in: Experimental & molecular medicine Vol. 53; no. 3; pp. 468 - 482
• Main Authors: Kim, Yo Na, Shin, Jae Hoon, Kyeong, Dong Soo, Cho, Soo Young, Kim, Mi-Young, Lim, Hee Jung, Jimenez, Maria Raquel Rojas, Kim, Il Yong, Lee, Mi-Ock, Bae, Yun Soo, Seong, Je Kyung
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.03.2021; Springer Nature B.V; 생화학분자생물학회
• Subjects: 13; 631/443/319/1642/2037; 631/80/304; 64/60; 82/80; 9/10; Adipose tissue; Animals; Biomedical and Life Sciences; Biomedicine; Cirrhosis; Diet, High-Fat - adverse effects; Fatty acids; Fatty liver; Fatty Liver - etiology; Fatty Liver - metabolism; Fatty Liver - pathology; Fatty Liver - prevention & control; Fibroblast growth factors; Fibroblast Growth Factors - agonists; Gene expression; Hepatocytes; High fat diet; Lipid Metabolism; Lipids; Lipogenesis; Liver cirrhosis; Liver diseases; Male; Medical Biochemistry; Membrane Proteins - physiology; Metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Molecular Medicine; Neoplasm Proteins - physiology; Nutrient deficiency; Obesity; Oxidation; Palmitic acid; Proteins; Steatosis; Stem Cells; Therapeutic applications; 생화학
• ISSN: 1226-3613; 2092-6413
• DOI: 10.1038/s12276-021-00573-3

The AHNAK nucleoprotein has been determined to exert an anti-obesity effect in adipose tissue and further inhibit adipogenic differentiation. In this study, we examined the role of AHNAK in regulating hepatic lipid metabolism to prevent diet-induced fatty liver. Ahnak KO mice have reportedly exhibited reduced fat accumulation in the liver and decreased serum triglyceride (TG) levels when provided with either a normal chow diet or a high-fat diet (HFD). Gene expression profiling was used to identify novel factors that could be modulated by genetic manipulation of the Ahnak gene. The results revealed that fibroblast growth factor 21 (FGF21) was markedly increased in the livers of Ahnak KO mice compared with WT mice fed a HFD. Ahnak knockdown in hepatocytes reportedly prevented excessive lipid accumulation induced by palmitate treatment and was associated with increased secretion of FGF21 and the expression of genes involved in fatty acid oxidation, which are primarily downstream of PPARα. These results indicate that pronounced obesity and hepatic steatosis are attenuated in HFD-fed Ahnak KO mice. This may be attributed, in part, to the induction of FGF21 and regulation of lipid metabolism, which are considered to be involved in increased fatty acid oxidation and reduced lipogenesis in the liver. These findings suggest that targeting AHNAK may have beneficial implications in preventing or treating hepatic steatosis. Liver disease: A potential treatment for nonalcoholic fatty liver A protein that modulates lipid accumulation could be a target for controlling nonalcoholic fatty liver disease (NAFLD). The AHNAK protein regulates fat cell development, and mice lacking AHNAK are less susceptible to obesity after being fed a HFD. South Korean researchers led by Je Kyung Seong of Seoul National University and Yun Soo Bae of Ewha Womans University, Seoul, have identified a mechanism by which AHNAK inhibition prevents lipid accumulation in NAFLD. The authors profiled gene expression in AHNAK-deficient mice, and noted a striking increase in levels of a signaling protein called FGF21 in the liver. This elevated FGF21 was in turn linked to increased breakdown and reduced production of fatty acids. Therapeutic interventions that inhibit AHNAK could help control NAFLD, a hard-to-treat condition that can ultimately lead to cirrhosis and liver failure.