Transgenic overexpression of CTRP3 prevents alcohol-induced hepatic triglyceride accumulation

Abstract

This study tested the ability of a novel adipose tissue derived cytokine, C1q TNF Related Protein 3 (CTRP3), to prevent alcohol-induced hepatic lipid accumulation, or alcoholic fatty liver disease (ALD). Previous work has demonstrated that CTRP3 is effective at preventing high fat diet-induced fatty liver, however, the potential of CTRP3 to inhibit ALD has not been explored. To test the potential protective effects of CTRP3, transgenic mice overexpressing CTRP3 (Tg) or wildtype littermates (WT) were subjected to one of two different models of ALD. In the first model, known as the NIAAA model, mice were fed control or alcohol-containing liquid diets (5% v/v) for 10 days followed by a single gavage of ethanol (5 g/kg). In the second model, the chronic model, mice were fed control or alcohol-containing diets for 6 weeks with no gavage. This study found that CTRP3 reduced triglyceride accumulation in the chronic model of alcohol consumption by ~50%, whereas no reduction was observed in the NIAAA model. Further analysis of isolated primary hepatocytes from WT and Tg mice demonstrated that CTRP3 increased oxygen consumption in the presence of fatty acids, indicating that CTRP3 increases hepatic fatty acid utilization. In conclusion, this study indicates that CTRP3 attenuates hepatic triglyceride accumulation in response to long-term chronic but not short-term alcohol consumption.

The sex specific effect of alcohol consumption on circulating levels of CTRP3

“…Thus, there has been renewed interest in developing effective therapeutic strategies to prevent alcoholic fatty liver disease [ 4 , 6 , 9 , 13 , 65 , 66 ]. Our data, combined with the finding that CTRP3 prevents alcohol-induced fatty liver disease [ 55 ], identifies CTRP3 as an ideal candidate to develop novel treatments for alcoholic fatty liver disease.…”

“…As CTRP3 levels are selectively reduced in ethanol fed female mice, this provides a novel mechanism to explore the increased susceptibility of females to alcoholic cirrhosis. Our previous work has shown that CTRP3 acts directly on liver tissue to stimulate lipid oxidation and attenuate both diet-induced and alcoholic fatty liver disease [ 38 , 55 ]. In support of this, CTRP3 levels are found to be lower in human patients with diet-induced hepatic steatosis, or non-alcoholic fatty liver disease [ 62 ].…”

“…Lipids were extracted as described by Bligh and Dyer and as previously performed [ 55 ]. Briefly, liver samples were weighed and homogenized in phosphate-buffered saline (10 ml/g tissue), followed by the addition of 1:2 (vol/vol) chloroform-methanol (3.75 ml/ml of sample homogenate).…”

High molecular weight, but not total, CTRP3 levels are associated with serum triglyceride levels

“…Transgenic overexpression of CTRP3 has been shown to prevent both alcoholic and nonalcoholic fatty liver disease in rodent studies (Peterson et al, ; Trogen et al, ). CTRP3 also reduces hepatic triglyceride synthesis and secretion, further supporting the role of CTRP3 in triglyceride regulation (Peterson et al, ).…”

“…The primary hypothesis was that, although total levels of circulating CTRP3 will be similar between people with type 2 diabetes compared with nondiabetic controls, there will be a difference between groups in the circulating oligomeric state of CTRP3. The secondary purpose of this study was to determine whether the circulating oligomeric state of CTRP3 correlates with the circulating levels of inflammatory cytokines or triglycerides as CTRP3 has been previously demonstrated to attenuate inflammation and to reduce triglyceride levels (Hofmann et al, ; Kopp, Bala, Buechler, et al, ; Kopp, Bala, Weigert, et al, ; Li et al, ; Petersen et al, ; Peterson et al, , ; Schmid, Kopp, Hanses, Karrasch, & Schaffler, ; Tan et al, ; Trogen et al, ; Yang et al, ; Yoo et al, ).…”