Caspase-1 deficiency in mice reduces intestinal triglyceride absorption and hepatic triglyceride secretion

Abstract

Obesity is accompanied by low-grade chronic systemic infl ammation characterized by increased circulating levels of proinfl ammatory cytokines, including interleukin (IL)-1 ␤ , tumor necrosis factor (TNF)-␣ , and IL-6 ( 1 ). Activation of infl ammatory pathways induces metabolic disturbances, leading to insulin resistance, dyslipidemia, and cardiovascular diseases. Caspase-1 is a cysteine protease that is known for its crucial role in the activation of the proinfl ammatory cytokines IL-18 and IL-1 ␤ . Additionally, caspase-1 has been shown to cleave other substrates, including proteins involved in energy metabolism ( 2-4 ). Caspase-1 activation is controlled by the infl ammasome, a multiprotein Abstract Caspase-1 is known to activate the proinfl ammatory cytokines IL-1 ␤ and IL-18. Additionally, it can cleave other substrates, including proteins involved in metabolism. Recently, we showed that caspase-1 defi ciency in mice strongly reduces high-fat diet-induced weight gain, at least partly caused by an increased energy production. Increased feces secretion by caspase-1-defi cient mice suggests that lipid malabsorption possibly further reduces adipose tissue mass. In this study we investigated whether caspase-1 plays a role in triglyceride-(TG)-rich lipoprotein metabolism using caspase-1-defi cient and wild-type mice. Caspase-1 defi ciency reduced the postprandial TG response to an oral lipid load, whereas TG-derived fatty acid (FA) uptake by peripheral tissues was not affected, demonstrated by unaltered kinetics of [ Lipid composition of fecesMice were individually housed for 4 days to determine food intake and collect feces quantitatively. Feces were weighed, freeze-dried, and ground, and fecal fatty acids (FA) were derivatized by methyl esterifi cation. Therefore, 2 ml methanol/hexane (4:1 v/v) containing 80 µg pentadecanoic acid (C15:0) as an internal standard (Fluka) was added to 15 mg of feces. Then, 200 µL acetyl chloride (Merck) was added, and samples were incubated at 95°C. After cooling to 4°C, 5 ml 6% K 2 CO 3 (Sigma) was added, and samples were centrifuged (10 min; 4,000 rpm, 4°C). The upper hexane layer was isolated and used for GC analysis of FA methyl esters (FAME). FAME were separated on a 50 m × 0.25 mm capillary GC column (CP Sil 88; Agilent technologies) in a 3800 GC gas chromatograph (Varian) equipped with a fl ame ionization detector. The injector and fl ame ionization detector were kept at 270°C. The column temperature was programmed from 170°C to 210°C. FAME were introduced by split injection (split ratio 20:1). Quantifi cation was based on the area ratio of the individual FA to the internal standard.To extract total cholesterol from feces, dried feces (10 mg) were incubated in 1 ml alkaline methanol (CH 3 OH: 1 M NaOH = 3:1 [v/v]) for 2 h at 80°C in screw-capped tubes using 5 ␣ -cholestane as internal standard. Tubes were cooled to room temperature, and the cholesterol was extracted twice with 2 ml petroleum ether. The combined petroleum ether layers were evaporated to dryness, and the ...

Role of caspase-1 in regulation of triglyceride metabolism

“…When challenged with a bolus of lipid, as might occur after a high-fat meal, caspase-1-deficient mice demonstrated dramatically accelerated clearance of lipid from plasma with no quantitative alteration of lipid production from the gut or liver. Surprisingly, these data contrast with the recently published work by van Diepen et al (37), in which the authors reported reduced TG absorption and reduced hepatic VLDL production. Of note, these authors used Triton, rather than poloxamer, to inhibit LPL and demonstrate altered VLDL production.…”

Anti-Inflammatory and Antiatherogenic Effects of the NLRP3 Inflammasome Inhibitor Arglabin in ApoE 2 .Ki Mice Fed a High-Fat Diet

“…Intestinal and hepatic gene expression analysis showed that caspase-1 deficiency did not affect fatty acid oxidation or fatty acid uptake but rather reduced intracellular fatty acid transport, thereby limiting lipid availability for the assembly and secretion of triglyceride-rich lipoproteins. 45 These results reveal a novel function for caspase-1 or caspase-1-cleaved substrates in controlling intestinal triglyceride absorption and hepatic triglyceride secretion.…”

“…Of note, in a recent publication, caspase-1 deficiency in mice was linked to intestinal lipid malabsorption. 45 In fact, oral gavage of [ 3 H] triglyceride-containing olive oil revealed that caspase-1 deficiency reduced triglyceride absorption and subsequent uptake of triglyceride-derived fatty acid in liver, muscle, and adipose tissue. Similarly, despite an elevated hepatic triglyceride content, caspase-1 deficiency reduced hepatic very-low-density lipoprotein and triglyceride production.…”

Oxidized tea polyphenols prevent lipid accumulation in liver and visceral white adipose tissue in rats

“…Rat underwent an oral fat tolerance test as previously described [25]. After an overnight fast, blood samples were obtained at 0, 1, 2, 3 and 5 h after the administration of an oral dose of olive oil (5 μL/g of body weight), olive oil and OTP (5 μL/g of body weight and 1 g/kg of body weight, respectively) and olive oil and OTP (5 μL/g of body weight and 2 g/kg of body weight, respectively) during 5 h. Nonesterified fatty acid (NEFA) and TAG were determined in plasma by enzymatic colorimetric methods according to the manufacturer's instructions (Nanjing Jiancheng Bioengineering).…”