CARBONIC ANHYDRASE MEDIATES HEPATIC STEATOSIS AND VASCULAR STIFFNESS INDUCED BY A WESTERN DIET

Abstract

The typical “Western diet” (WD) is higher in fat and high fructose corn syrup when compared to a healthful diet (CD) that is lower in fat and does not contain high fructose corn syrup. A WD leads to insulin resistance and the metabolic syndrome that is characterized by fatty steatosis in the liver, a precursor of non‐alcoholic fatty liver disease, and vascular stiffness that presages atherosclerotic vascular disease and hypertension. Bicarbonate is a necessary precursor for fatty acid synthesis and the storage of depot fat in the liver and in perivascular tissue. We hypothesized that acetazolamide (ACT), a carbonic anhydrase inhibitor that blocks bicarbonate‐dependent formation of fatty acids and triglycerides, could prevent the fatty steatosis and vascular stiffness that is induced by a WD. Laboratory mice were fed a WD (46% kcals from fat; 36% kcals from carbohydrate, sucrose [17.5%] and high fructose corn syrup [17.5%]) or CD (10% kcals from fat; 72% kcals from carbohydrate; no high fructose corn syrup) for sixteen weeks with, and without, 2mM ACT in the drinking water ad libitum. Subsequently, rodents were weighed, and fat mass, lean mass, and body water was measured with magnetic resonance imaging (MRI). Hepatic steatosis was graded on a scale of 1–9 arbitrary units (A.U.) on hematoxylin and eosin stained liver tissue. Vascular stiffness was measured by atomic force microscopy (AFM) on aorta explants. CD WD WD + ACT Total Body Weight (values in g ± SEM) 23.1 ± 0.4 31.3 ± 1.1** 20.1 ± 1.5 (N.S.) Total Fat Mass (values in g ± SEM) 4.7 ± 11.2 11.2 ± 1 ** 5.1 ± 1.2 (N.S.) Total Body Water/Total Body Weight (in % ± SEM) 65.1 ± 0.8 49.9 ± 2.0** 57.9 ± 2.6 (N.S.) Hepatic Steatosis (in arbitrary units, AU, ± SEM) 3.75 ± 1.4 7.4 ± 0.5* 5.0 ± 1.1 (N.S.) Vascular Stiffness (in kPa ± SEM) 4.72 ± 0.6 17.18 ± 3.2* 5.22 ± 1.0 (N.S.) N = 20, denotes P < 0.05, denotes P < 0.01, N.S. denotes not significantly different from control diet (CD). Compared to a CD, sixteen weeks of a WD was associated with a gain in total body weight that was completely inhibited by ACT. The increase in total adipocyte fat mass and percentage of body weight from water in WD animals were also inhibited by ACT. Notably, inhibition of carbonic anhydrase resulted in a decrease in hepatic steatosis and aortic vascular stiffness. If excess adiposity is responsible for the untoward sequelae of the metabolic syndrome, chronic inhibition of carbonic anhydrase‐dependent formation of bicarbonate and fatty acid synthesis could result in the normalization of the metabolic profile associated with an unhealthy Western dietSupport or Funding InformationSupport for this project was provided by the University of Missouri.