Cholestasis and hypercholesterolemia in SCD1-deficient mice fed a low-fat, high-carbohydrate diet

Abstract

Stearoyl-coenzyme A desaturase 1-deficient (SCD1 2/2 ) mice have impaired MUFA synthesis. When maintained on a very low-fat (VLF) diet, SCD12/2 mice developed severe hypercholesterolemia, characterized by an increase in apolipoprotein B (apoB)-containing lipoproteins and the appearance of lipoprotein X. The rate of LDL clearance was decreased in VLF SCD1 2/2 mice relative to VLF SCD11/1 mice, indicating that reduced apoB-containing lipoprotein clearance contributed to the hypercholesterolemia. Additionally, HDL-cholesterol was dramatically reduced in these mice. The presence of increased plasma bile acids, bilirubin, and aminotransferases in the VLF SCD1 2/2 mice is indicative of cholestasis. Supplementation of the VLF diet with MUFA-and PUFA-rich canola oil, but not saturated fat-rich hydrogenated coconut oil, prevented these plasma phenotypes. However, dietary oleate was not as effective as canola oil in reducing LDL-cholesterol, signifying a role for dietary PUFA deficiency in the development of this phenotype. These results indicate that the lack of SCD1 results in an increased requirement for dietary unsaturated fat to compensate for impaired MUFA synthesis and to prevent hypercholesterolemia and hepatic dysfunction. Therefore, endogenous MUFA synthesis is essential during dietary unsaturated fat insufficiency and influences the dietary requirement of PUFA. Although dietary saturated fat is generally regarded as hypercholesterolemic, the roles of de novo synthesized saturated fatty acids and MUFAs in the regulation of plasma cholesterol levels have not been thoroughly investigated (1-3). Stearoyl-coenzyme A desaturase 1 (SCD1) is a central enzyme in lipid metabolism that catalyzes the desaturation of palmitoyl-CoA and stearoyl-CoA to palmitoleoyl-CoA and oleoyl-CoA, respectively (4). The dietary requirement for MUFA, if any, is confounded by the capacity for endogenous MUFA synthesis. Furthermore, under certain metabolic conditions, both dietary and endogenously synthesized MUFAs have been hypothesized to influence the dietary requirement for certain PUFAs (5). SCD1-deficient (SCD1 2/2 ) mice have impaired MUFA synthesis and are a useful animal model to study the influence of de novo synthesized MUFAs on lipoprotein metabolism and the requirement for dietary unsaturated fat.Four SCD isoforms (SCD1-SCD4), encoded by different genes, have been identified in the mouse (4). However, SCD1 is the most abundant isoform expressed in lipogenic tissues, such as liver and adipose tissue (4). SCD1 gene expression is regulated by both hormones (insulin, leptin) and by a variety of nutrients such as cholesterol, glucose, fructose, and PUFAs (4, 6-11). This transcriptional regulation involves several transcription factors, including carbohydrate response element binding protein, sterolregulatory element binding protein-1c (SREBP-1c), and liver X receptor, highlighting the importance of SCD1 activity for the adaptation to different metabolic demands (12, 13). SCD1 activity influences the fatty acid composi-

Low hepatic stearoyl-CoA desaturase 1 activity is associated with fatty liver and insulin resistance in obese humans

“…However, these lean SCD1-deficient mice developed severe hypercholesterolaemia, had a large decrease in HDLcholesterol levels and displayed lower VLDL production than the wild-type on a low-fat, high-carbohydrate diet [27]. This finding implies that liver-specific downregulation of SCD1 may impair VLDL assembly and thus may abolish the capacity of the liver to clear intrahepatic TG.…”

“…In addition, total SCD1 deficiency resulted in a noticeable phenotype with alopecia [44], abnormalities in the epidermal lipid barrier leading to breakdown of thermoregulation and a metabolic wasting syndrome that could in part explain the excessive energy expenditure [45]. Moreover, SCD1-deficient mice on a low-fat, high-carbohydrate diet developed severe hypercholesterolaemia and had a large decrease in HDL-cholesterol levels [27]. In this respect it is also important to mention that loss of hepatic SCD1 activity leads to significantly lower VLDL-TG content in vivo and TG secretion in isolated hepatocytes [18,46].…”

Inhibition of stearoyl CoA desaturase activity induces hypercholesterolemia in the cholesterol-fed hamster

“…This was in marked contrast to the situation in which SO was fed together with cholesterol and plasma ALT was increased 20-fold. Paradoxically, Flowers et al (26) reported similar liver damage, and raised plasma free cholesterol concentrations in SCD 2/2 mice fed cholesterol-free, very low fat diets. This was also associated with changes in plasma bile acids and bilirubin, which the authors attributed to cholestasis, possibly as a result of altered membrane fatty acid composition.…”

Altered Fatty Acid Profile in the Liver and Serum of Stroke-Prone Spontaneously Hypertensive Rats: Reduced Proportion of cis-Vaccenic Acid

“…After visualization by spraying 0.001 w/v primuline in 80 acetone, the regions that corresponded to TAG were scraped off and transferred to tubes. TAG was extracted from silica gel as described previously 29 , and determined by an enzymatic method using a commercially available kit Triglyceride E-Test Wako; Wako Pure Chemical Industries, Ltd., Osaka, Japan essentially according to Flowers et al 34 . TAG in serum was directly determined by the enzymatic method mentioned above.…”