CGI-58 knockdown in mice causes hepatic steatosis but prevents diet-induced obesity and glucose intolerance

Abstract

In chow-fed mice, ASO-mediated depletion of CGI-58 did not alter weight gain, plasma TG, or plasma glucose, yet raised hepatic TG levels ‫ف‬ 4-fold. When challenged with a high-fat diet (HFD), CGI-58 ASO-treated mice were protected against diet-induced obesity, but their hepatic contents of TG, diacylglycerols, and ceramides were all elevated, and intriguingly, their hepatic phosphatidylglycerol content was increased by 10-fold. These hepatic lipid alterations were associated with signifi cant decreases in hepatic TG hydrolase activity, hepatic lipoprotein-TG secretion, and plasma concentrations of ketones, nonesterifi ed fatty acids, and insulin. Additionally, HFD-fed CGI-58 ASO-treated mice were more glucose tolerant and insulin sensitive.

Dissociation between fatty liver and insulin resistance: the role of adipose triacylglycerol lipase

“…Very similar results were published recently by Brown et al [18] using antisense oligonucleotides to inhibit expression of the comparative gene identification-58 (Cgi-58 [also known as Abhd5]). The protein CGI-58, also known as α/β Fig.…”

Insulin receptor Thr1160 phosphorylation mediates lipid-induced hepatic insulin resistance

“…Many studies have dissociated hepatic triglyceride and DAG accumulation from hepatic insulin resistance (6). For example, mice lacking the adipose triglyceride lipase (ATGL) cofactor CGI-58 develop massive hepatic steatosis and elevated DAG levels, yet retain hepatic insulin sensitivity (9). Similar phenotypes are observed in mice with defective VLDL secretion owing to knockout of microsomal triglyceride transfer protein (Mttp) (8) and mice with liver-specific deletion of histone deacetylase 3 (Hdac3) (7).…”

“…Several rodent models with preserved hepatic insulin sensitivity despite hepatic steatosis raise the possibility that NAFLD does not cause hepatic insulin resistance (6)(7)(8)(9)(10). Hepatic insulin resistance has even been proposed to drive hepatic steatosis, though a plausible mechanism for this direction of causality is lacking (6,11).…”

The impact of genetic stress by ATGL deficiency on the lipidome of lipid droplets from murine hepatocytes

“…Importantly, diseases are known to be caused by inactive ATGL protein due to a genetic defect (neutral lipid storage disease with myopathy) ( 23 ), or to be caused by functional ATGL yet inactive by lack of functional coactivator CGI-58 (neutral lipid storage disease with ichtyosis, Chanarin-Dorfman syndrome) ( 24 ). In either case, enhanced liver TG levels were observed, but without insulin resistance and glucose intolerance ( 25 ). We daresay that these diseases will have a clearly distinguishable phenotypic imprint on the hepatocyte lipidome.…”