An Underlying Mechanism by which Hepatic Steatosis Drives the Development of Hypertension

Hepatic steatosis, a consequence of obesity, is closely associated with metabolic and cardiovascular diseases, including hypertension. Even in patients that are not hypertensive, the amount of fat in the liver is positively associated with blood pressure. We hypothesized there was an underlying mechanism linking excess fat in the liver with increased blood pressure. We have previously established that liver lipid content is positively associated with hepatic production and release of the inhibitory neurotransmitter GABA, a process dependent on both the GABA shunt and electrogenic GABA transporters. Because GABA is co-transported with 1-2 net positive charges, hepatocyte depolarization, common in obesity, encourages hepatocyte GABA release. To investigate the effect of hepatocyte depolarization, we used an adeno-associated virus to induce hepatocyte specific expression of an artificial chimeric channel that opens in the presence of an exogenous ligand causing depolarization. Inducing hepatocyte depolarization increases release of GABA and decreases hepatic vagal afferent nerve activity. We established that administering the depolarizing ligand acutely (15-40 minutes after IP administration) increased systolic (30.08 ± 5.6 mmHg), diastolic (16.47 + 4.3 mmHg), and mean blood pressure (17.85 + 4.4 mmHg) measured via telemetry devices. In hepatic vagotomized mice hepatocyte depolarization had no effect on blood pressure, establishing the key role of afferent hepatic vagal signals in regulating blood pressure. Pharmacological inhibition of the GABA shunt by daily administration of ethanolamine-O-sulfate (4 days; 8 mg/mouse/day) limited liver slice GABA release and decreased systolic, diastolic, and mean (10 ± 3.07 mmHg; P < 0.05) blood pressure in diet-induced obese mice during the first hour of the dark cycle. We subsequently knocked down GABA-transaminase with bi-weekly IP deliver of an anti-sense oligonucleotide targeted to GABA-transaminase (12.5 mg/kg). We have previously established that this decreases liver GABA-transaminase mRNA expression by 97% without affecting mRNA expression in the pancreas or brain. GABA-transaminase knockdown decreased 24h mean, systolic, and diastolic blood pressure (17 + 3, 20 +2, and 14 + 4 mmHg respectively) in obese, angiotensin II induced hypertensive (continuous delivery of angiotensin II 800 ng/kg/min by Alzet® osmotic minipump) male mice. Together this data supports a role of hepatocyte GABA production and release in the hypertension that accompanies obesity. Moreover, our results provide a mechanism by which hepatic lipid content can affect blood pressure, identifying potential targets for the treatment and prevention of obesity-induced hypertension. © FASEB.