Mechanisms linking obesity, chronic kidney disease, and fatty liver disease: the roles of fetuin-A, adiponectin, and AMPK

Abstract

Obesity is a risk factor for chronic kidney disease (CKD) and nonalcoholic fatty liver disease (NAFLD). Recent studies identify mechanisms common to both diseases linked through an interorgan communication orchestrated by fetuin-A and adiponectin. In liver and kidney, the energy sensor 5'-AMP activated protein kinase (AMPK) is pivotal to directing podocytes and hepatocytes to compensatory and potentially deleterious pathways, leading to inflammatory and profibrotic cascades culminating in end-organ damage. Regulation of these early upstream pathways may provide new therapeutic targets for these increasingly common sequelae of obesity.

Figure 1.

There is an inverse correlation between serum fetuin-A levels and adiponectin in patients with stable cardiovascular disease. The association was adjusted for age, sex, race, body mass index, and estimated GFR among a population of 963 outpatients (n = 242 or 243 per quartile). Mean estimated GFR = 71 ml/min/1.73 m² (29% with estimated GFR < 60, none with ESRD). The unadjusted Spearmen correlation (r = −0.27; P < 0.001). Error bars reflect 95% confidence intervals.

Figure 2.

With caloric excess, there is fatty acid excess and insulin resistance fueling hepatic triacylglycerol synthesis and steatosis. Caloric excess and/or a fatty liver may lead to greater serum fetuin-A levels. Higher fetuin-A levels lead to suppression of adiponectin transcription in adipocytes through direct mechanisms and potentially indirectly through an expansion of adipose tissue. Excess caloric intake and lower adiponectin reduces AMPK activation, promoting hepatic stellate cell proliferation and generation of reactive oxygen species in the liver, leading to conversion from hepatic steatosis to steatohepatitis and ultimately cirrhosis. Through similar pathways, lower adiponectin levels reduce AMPK in podocytes to promote podocyte foot process effacement and albuminuria.