Activation of renal peroxisome proliferator-activated receptor α (PPARα) is renoprotective, but there is no safe PPARα activator for patients with chronic kidney disease (CKD). Studies have reported that irbesartan (Irbe), an angiotensin II receptor blocker (ARB) widely prescribed for CKD, activates hepatic PPARα. However, Irbe's renal PPARα-activating effects and the role of PPARα signalling in the renoprotective effects of Irbe are unknown. Herein, these aspects were investigated in healthy kidneys of wild-type (WT) and Ppara -null (KO) mice and in the murine protein-overload nephropathy (PON) model respectively. The results were compared with those of losartan (Los), another ARB that does not activate PPARα. PPARα and its target gene expression were significantly increased only in the kidneys of Irbe-treated WT mice and not in KO or Los-treated mice, suggesting that the renal PPARα-activating effect was Irbe-specific. Irbe-treated-PON-WT mice exhibited decreased urine protein excretion, tubular injury, oxidative stress (OS), and pro-inflammatory and apoptosis-stimulating responses, and they exhibited maintenance of fatty acid metabolism. Furthermore, the expression of PPARα and that of its target mRNAs encoding proteins involved in OS, pro-inflammatory responses, apoptosis and fatty acid metabolism was maintained upon Irbe treatment. These renoprotective effects of Irbe were reversed by the PPARα antagonist MK886 and were not detected in Irbe-treated-PON-KO mice. These results suggest that Irbe activates renal PPARα and that the resultant increased PPARα signalling mediates its renoprotective effects.

The adipocyte life cycle hypothesis states that the metabolic properties of an adipocyte vary predictably during its life cycle: that as an adipocyte matures, it accumulates triacylglycerol (triglyceride) and becomes larger; that the rates of triacylglycerol synthesis and lipolysis are matched within adipocytes and that larger adipocytes, in general, have greater rates of triacylglycerol synthesis and, concurrently, greater rates of lipolysis and, therefore, larger adipocytes have greater rates of transmembrane fatty acid flux; and that the secretion of cytokines can also be related to adipocyte size with larger adipocytes having a more unfavourable profile of cytokine secretion than smaller adipocytes. Adipocyte location is an important modifier of this relationship and the favoured sites of adipocyte proliferation are a function of gender and the position within the life cycle of the organism at which proliferation occurs. The adipocyte life cycle hypothesis posits that the metabolic consequences of obesity depend on whether expansion of adipose tissue is achieved primarily by an increase in adipocyte number or adipocyte size. This hypothesis may explain a variety of previously unanswered clinical puzzles such as the vulnerability of many peoples from South East Asia to the adverse metabolic consequences of obesity.

We evaluated the clinical significance of serum carnitine concentrations in determining the severity of impaired myocardial fatty acid metabolism in idiopathic hypertrophic cardiomyopathy (HCM). We studied 56 asymptomatic or mildly symptomatic patients with HCM. Serum levels of free carnitine and acylcarnitine were measured by the enzymic cycling method. Myocardial scintigraphy with 123 I-labelled 15-( p -iodophenyl)-3- R , S -methylpentadecanoic acid (BMIPP) was performed, and the images were analysed quantitatively and semi-quantitatively. Serum free carnitine levels were significantly higher in HCM patients than in normal subjects (52.5±9.5 and 42.3±5.5 nmol/ml respectively; P < 0.0001). On the other hand, serum acylcarnitine levels and acyl/free carnitine ratios were lower in HCM patients than in normal subjects (10.2±4.0 nmol/ml and 0.19±0.08, compared with 13.2±3.9 nmol/ml and 0.32±0.11 respectively; P < 0.0001). Clinical characteristics were not significantly different between the patients showing high and normal free carnitine levels, although female patients with high free carnitine levels were few ( P = 0.02). Both quantitative and semi-quantitative analyses revealed that the severity of decreased myocardial BMIPP uptake was significantly correlated with serum free carnitine levels (quantitative analysis: r = -0.422, P < 0.0012; semi-quantitative analysis: r = 0.633, P < 0.0001). In the presence of reduced carnitine uptake into the myocardium in HCM, there may also be reduced transport of acylcarnitines out of the myocardium into the plasma. Although inborn errors of fatty acid metabolism and carnitine deficiencies are reported to provoke secondary HCM and are associated with low serum carnitine concentrations, this study has revealed that the levels of carnitine are, in contrast, increased in idiopathic HCM. Moreover, serum carnitine concentrations are a sensitive indicator of the severity of impaired myocardial fatty acid metabolism even in asymptomatic patients with HCM.

1. Forearm arterial and venous concentrations of free carnitine, short-chain acylcarnitine, long-chain acylcarnitine, glucose, lactate, pyruvate, alanine, non-esterified fatty acids, glycerol, 3-hydroxybutyrate and acetoacetate were measured in fasted adult subjects. 2. In all subjects there was net uptake of short-chain acylcarnitine, 3-hydroxybutyrate and acetoacetate and net release of free carnitine and non-esterified fatty acids. The arteriovenous differences of the other metabolites were not consistent. 3. These observations support the concept that short-chain acylcarnitine (largely acetylcarnitine) contributes to the flux of metabolic fuels from the liver to muscle in the fasted state, although to a limited extent in comparison with 3-hydroxybutyrate (< 5% on a molar basis).

1. The activities of carnitine acyltransferases and acyl-CoA hydrolases were determined in human and rat liver to establish the validity of extrapolating from studies on rats to human metabolism. 2. In human liver, carnitine acetyltransferase activity was 10–14 times higher and carnitine octanoyltransferase 1.7–2.4 times higher than in rat liver, while carnitine palmitoyltransferase activity was similar in human and rat. 3. Acetyl-CoA hydrolase and octanoyl-CoA hydrolase activities were lower in human (42–57%) than in rat liver, but palmitoyl-CoA hydrolase activity was similar in both species. 4. The activity of citrate synthase was lower (44%) in human than in rat liver. The low citrate synthase activity and the high carnitine acetyltransferase in human liver suggest that in man acetylcarnitine might be more important as a vehicle for export of acetyl units from mitochondria than citrate. 5. The high activity of carnitine acetyltransferase in human liver is consistent with the observation that acetylcarnitine is the predominant acylcarnitine excreted in diabetic ketosis in man. 6. It is concluded that the rat may not be a valid model for carnitine metabolism in man, and that in human liver carnitine may have an important role in transfer of acetyl groups out of mitochondria and possibly also to extrahepatic tissues.