Chronic angiotensin receptor activation promotes hepatic triacylglycerol accumulation during an acute glucose challenge in obese-insulin-resistant OLETF rats

Abstract

Purpose Angiotensin receptor blockers (ARBs) can ameliorate metabolic syndrome (MetS)-associated dyslipidemia, hepatic steatosis, and glucose intolerance, suggesting that angiotensin receptor (AT1) over-activation contributes to impaired lipid and glucose metabolism, which is characteristic of MetS. The aim of this study was to evaluate changes in the lipid profile and proteins of fatty acid uptake, triacylglycerol (TAG) synthesis, and β-oxidation to better understand the links between AT1 overactivation and non-alcoholic fatty liver disease (NAFLD) during MetS. Methods Four groups of 25-week-old-rats were used: (1) untreated LETO, (2) untreated OLETF, (3) OLETF + angiotensin receptor blocker (ARB; 10 mg olmesartan/kg/d × 8 weeks) and (4) OLETF ± ARB (MINUS; 10 mg olmesartan/kg/d × 4 weeks, then removed until dissection). To investigate the dynamic shifts in metabolism, animals were dissected after an oral glucose challenge (fasting, 3 and 6 h post-glucose). Results Compared to OLETF, plasma total cholesterol and TAG remained unchanged in ARB. However, liver TAG was 55% lesser in ARB than OLETF, and remained lower throughout the challenge. Basal CD36 and ApoB were 28% and 29% lesser, respectively, in ARB than OLETF. PRDX6 abundance in ARB was 45% lesser than OLETF, and it negatively correlated with liver TAG in ARB. Conclusions Chronic blockade of AT1 protects the liver from TAG accumulation during glucose overload. This may be achieved by modulating NEFA uptake and increasing TAG export via ApoB. Our study highlights the contributions of AT1 signaling to impaired hepatic substrate metabolism and the detriments of a high-glucose load and its potential contribution to steatosis during MetS.

Factors Associated with Liver Fibrosis in Chinese Patients with Type 2 Diabetes Mellitus and Non-Alcoholic Fatty Liver Disease

“… 38 Meanwhile, Ang II can aggravate IR though activating insulin signaling pathways. 39 Yuan et al 40 found that mice with hypertension showed more severe LF than those without hypertension, and that cytokine activation and inflammation played an important role. RAS activation, IR, and inflammation are important pathophysiological mechanisms underlying the co-morbidity of hypertension and NAFLD.…”

Angiotensin receptor blockade with olmesartan alleviates brain pathology in obese OLETF rats

“…Thus, some analyses were performed in younger animals initially to gain further insights. Basic metabolic changes are summarized in Table 2 18,22,25,26 . In brief, all presented parameters were elevated in OLETF rats at 16 weeks of age when compared to age‐matched control (LETO) rats and ARB treatment normalized the elevated SBP and plasma glucose levels.…”

“…Younger animals were 10 week old males divided into the following groups: (1) untreated control + vehicle (0.5% methylcellulose by oral gavage once daily), (2) untreated OLETF + vehicle, and (3) OLETF + ARB (ARB; 10 mg olmesartan/kg/day by oral gavage × 6 weeks) and were approximately 16 weeks at dissection 18,22 . Older animals were 17 week old males divided into the same three groups with the exception that older animals were treated with ARB for 8 weeks and were ~25 weeks at dissection 25,26 . Olmesartan was selected as the ARB of choice in the primary studies because it is more effective at ameliorating T2D‐associated renal injury and hypertension than other ARBs 60 .…”

“…At 16 weeks of age, male OLETF rats present with early onset of insulin resistance and the associated hyperglycemia along with modest progression of other metabolic phenotypes characteristic of the model such as adiposity, dyslipidemia, and hypertension 18,22,23 . By 25 weeks of age, virtually all male OLETF rats develop frank type II diabetes and advanced adiposity and hypertension among other metabolic defects 23,25,26 . Thus, this model allowed us to study potential effects of the manifestation of dysmetabolism and the contribution of AT1 signalling on neural defects with respect to the distinct stage of MetS as defined by the difference in age.…”

“…18,22,23 By 25 weeks of age, virtually all male OLETF rats develop frank type II diabetes and advanced adiposity and hypertension among other metabolic defects. 23,25,26 Thus, this model allowed us to study potential effects of the manifestation of dysmetabolism and the contribution of AT1 signalling on neural defects with respect to the distinct stage of MetS as defined by the difference in age. The MetS phenotypes including the associated obesity are primarily induced by the hyperphagia caused by a mutation in the CCKAR gene, which encodes for the cholecystokinin-1 (CCK-1) receptor.…”