CAT‐2003: A novel sterol regulatory element‐binding protein inhibitor that reduces steatohepatitis, plasma lipids, and atherosclerosis in apolipoprotein E*3‐Leiden mice

Abstract

CAT‐2003 is a novel conjugate of eicosapentaenoic acid (EPA) and niacin designed to be hydrolyzed by fatty acid amide hydrolase to release EPA inside cells at the endoplasmic reticulum. In cultured liver cells, CAT‐2003 blocked the maturation of sterol regulatory element‐binding protein (SREBP)‐1 and SREBP‐2 proteins and decreased the expression of multiple SREBP target genes, including HMGCR and PCSK9. Consistent with proprotein convertase subtilisin/kexin type 9 (PCSK9) reduction, both low‐density lipoprotein receptor protein at the cell surface and low‐density lipoprotein particle uptake were increased. In apolipoprotein E*3‐Leiden mice fed a cholesterol‐containing western diet, CAT‐2003 decreased hepatic inflammation and steatosis as evidenced by fewer inflammatory cell aggregates in histopathologic sections, decreased nuclear factor kappa B activity in liver lysates, reduced inflammatory gene expression, reduced intrahepatic cholesteryl ester and triglyceride levels, and decreased liver mass. Plasma PCSK9 was reduced and hepatic low‐density lipoprotein receptor protein expression was increased; plasma cholesterol and triglyceride levels were lowered. Aortic root segments showed reduction of several atherosclerotic markers, including lesion size, number, and severity. CAT‐2003, when dosed in combination with atorvastatin, further lowered plasma cholesterol levels and decreased hepatic expression of SREBP target genes. Conclusion: SREBP inhibition is a promising new strategy for the prevention and treatment of diseases associated with abnormal lipid metabolism, such as atherosclerosis and nonalcoholic steatohepatitis. (Hepatology Communications 2017;1:311–325)

Key Inflammatory Processes in Human NASH Are Reflected in Ldlr−/−.Leiden Mice: A Translational Gene Profiling Study

“…Given this large diversity of disease-inducing mechanisms in human NASH, it is unlikely that one single preclinical model for NASH will reflect the entire spectrum of underlying molecular responses observed in patients. However, individual models may recapitulate specific aspects of the spectrum of molecular responses seen in humans and can be of value to study that particular mechanism (Morrison et al, 2015 ; Iruarrizaga-Lejarreta et al, 2017 ; Zimmer et al, 2017 ). At the same time, one must always be aware of the limitations of the model employed.…”

“…At the same time, one must always be aware of the limitations of the model employed. The Ldlr −/− .Leiden model for instance, while mimicking many aspects of human NASH (e.g., pathophysiology, histology, underlying molecular processes; Liang et al, 2014 ; Morrison et al, 2016 ; Mulder et al, 2016 ; van Koppen et al, 2018 ), is unsuitable to study interventions that require a functioning LDL receptor (Zimmer et al, 2017 ). Although many different (diet-inducible) experimental models of NASH have been reported (reviewed elsewhere Takahashi et al, 2012 ), the vast majority of these models has only been characterized on the pathophysiological and histological level and thus their value in the study of human disease processes remains unclear and requires further investigation.…”

Sex-Specific Differences in Fat Storage, Development of Non-Alcoholic Fatty Liver Disease and Brain Structure in Juvenile HFD-Induced Obese Ldlr-/-.Leiden Mice

“…The liver was cut into 3 µm-thick cross sections and stained with haematoxylin and eosin for histopathological analysis of NAFLD. Development of NAFLD was scored in two cross-sections per mouse, by a board-certified pathologist (blinded for condition) using a well-established scoring system for rodent NAFLD [32] as previously described [33]. Briefly, macrovesicular steatosis, microvesicular steatosis and hepatocellular hypertrophy were expressed as the percentage of the total liver section affected.…”

Arid1a Loss Drives Nonalcoholic Steatohepatitis in Mice Through Epigenetic Dysregulation of Hepatic Lipogenesis and Fatty Acid Oxidation

“…Given the fact lipogenesis is promoted in the Arid1a ‐deficient state, we wanted to determine if this might be a therapeutic target for NASH progression within the more aggressive Arid1a / Pten double KO model. To that end, we treated double KO mice with CAT‐2003, an orally bioavailable small molecule that inhibits SREBP maturation and activation of SREBP target genes . SREBP‐1c is an attractive target for this double KO model because it is known to be a master regulator of enzymes in the de novo lipogenesis pathway .…”