SCD1 deficiency protects mice against ethanol-induced liver injury.

Stearoyl-CoA desaturase 1 (SCD1) is a delta-9 fatty acid desaturase that catalyzes the synthesis of mono-unsaturated fatty acids (MUFA). SCD1 is a critical control point regulating hepatic lipid synthesis and β-oxidation. Scd1 KO mice are resistant to the development of diet-induced non-alcoholic fatty liver disease (NAFLD). Using a chronic-binge protocol of ethanol-mediated liver injury, we aimed to determine if these KO mice are also resistant to the development of alcoholic fatty liver disease (AFLD). Mice fed a low-fat diet (especially low in MUFA) containing 5% ethanol for 10days, followed by a single ethanol (5g/kg) gavage, developed severe liver injury manifesting as hepatic steatosis. This was associated with an increase in de novo lipogenesis and inflammation. Using this model, we show that Scd1 KO mice are resistant to the development of AFLD. Scd1 KO mice do not show accumulation of hepatic triglycerides, activation of de novo lipogenesis nor elevation of cytokines or other pro-inflammatory markers. Incubating HepG2 cells with a SCD1 inhibitor induced a similar resistance to the effect of ethanol, confirming a role for SCD1 activity in mediating ethanol-induced hepatic injury. Taken together, our study shows that SCD1 is a key player in the development of AFLD and associated deleterious effects, and suggests SCD1 inhibition as a therapeutic option for the treatment of this hepatic disease.

Lounis MA ，Escoula Q ，Veillette C ，Bergeron KF ，Ntambi JM ，Mounier C ... -  《-》

Hepatic stearoyl-CoA desaturase-1 deficiency induces fibrosis and hepatocellular carcinoma-related gene activation under a high carbohydrate low fat diet.

Stearoyl-CoA desaturase-1 (SCD1) is a pivotal enzyme in lipogenesis, which catalyzes the synthesis of monounsaturated fatty acids (MUFA) from saturated fatty acids, whose ablation downregulates lipid synthesis, preventing steatosis and obesity. Yet deletion of SCD1 promotes hepatic inflammation and endoplasmic reticulum stress, raising the question of whether hepatic SCD1 deficiency promotes further liver damage, including fibrosis. To delineate whether SCD1 deficiency predisposes the liver to fibrosis, cirrhosis, and hepatocellular carcinoma (HCC), we employed in vivo SCD1 deficient global and liver-specific mouse models fed a high carbohydrate low-fat diet and in vitro established AML12 mouse cells. The absence of liver SCD1 remarkably increased the saturation of liver lipid species, as indicated by lipidomic analysis, and led to hepatic fibrosis. Consistently, SCD1 deficiency promoted hepatic gene expression related to fibrosis, cirrhosis, and HCC. Deletion of SCD1 increased the circulating levels of Osteopontin, known to be increased in fibrosis, and alpha-fetoprotein, often used as an early marker and a prognostic marker for patients with HCC. De novo lipogenesis or dietary supplementation of oleate, an SCD1-generated MUFA, restored the gene expression related to fibrosis, cirrhosis, and HCC. Although SCD1 deficient mice are protected against obesity and fatty liver, our results show that MUFA deprivation results in liver injury, including fibrosis, thus providing novel insights between MUFA insufficiency and pathways leading to fibrosis, cirrhosis, and HCC under lean non-steatotic conditions.

Ntambi JN ，Kalyesubula M ，Cootway D ，Lewis SA ，Phang YX ，Liu Z ，O'Neill LM ，Lefers L ，Huff H ，Miller JR ，Pegkou Christofi V ，Anderson E ，Aljohani A ，Mutebi F ，Dutta M ，Patterson A ，Ntambi JM ... -  《-》

Oleate activates SREBP-1 signaling activity in SCD1-deficient hepatocytes.

Stearoyl-CoA desaturase-1 (SCD1) is a key player in lipid metabolism. SCD1 catalyzes the synthesis of monounsaturated fatty acids (MUFA). MUFA are then incorporated into triacylglycerols and phospholipids. Previous studies have shown that Scd1 deficiency in mice induces metabolic changes in the liver characterized by a decrease in de novo lipogenesis and an increase in β-oxidation. Interestingly, Scd1-deficient mice show a decrease in the expression and maturation of the principal lipogenic transcription factor sterol receptor element binding protein-1 (SREBP-1). The mechanisms mediating this effect on de novo lipogenesis and β-oxidation have not been fully elucidated. We evaluated the role of SCD1 on de novo lipogenesis and β-oxidation in HepG2 cells. We also used Scd1-deficient mice and two strains of transgenic mice that produce either oleate (GLS5) or palmitoleate (GLS3) in a liver-specific manner. We demonstrate that the expression of β-oxidation markers increases in SCD1-deficient hepatocytes and suggest that this is due to an increase in cellular polyunsaturated fatty acid content. We also show that the changes in the level of SREBP-1 expression, for both the precursor and the mature forms, are mainly due to the lack of oleate in SCD1-deficient hepatocytes. Indeed, oleate treatment of cultured HepG2 cells or hepatic oleate production in chow-fed GLS5 mice can restore SREBP-1 expression and increase hepatic de novo lipogenesis. Finally, we show that oleate specifically increases SREBP-1 nuclear accumulation, suggesting a central role for oleate in SREBP-1 signaling activity.

Lounis MA ，Bergeron KF ，Burhans MS ，Ntambi JM ，Mounier C ... -  《-》

Hepatic stearoyl CoA desaturase 1 deficiency increases glucose uptake in adipose tissue partially through the PGC-1α-FGF21 axis in mice.

Increased carbohydrate consumption increases hepatic de novo lipogenesis, which has been linked to the development of chronic metabolic diseases, including obesity, hepatic steatosis, and insulin resistance. Stearoyl CoA desaturase 1 (SCD1) is a critical lipogenic enzyme that catalyzes the synthesis of two monounsaturated fatty acids, oleate and palmitoleate, from the saturated fatty acids stearate and palmitate, respectively. SCD1-deficient mouse models are protected against diet-induced adiposity, hepatic steatosis, and hyperglycemia. However, the mechanism of this protection by SCD1 deficiency is unclear. Using liver-specific SCD1 knockout (LKO) mice fed a high-carbohydrate, low-fat diet, we show that hepatic SCD1 deficiency increases systemic glucose uptake. Hepatic SCD1 deficiency enhanced glucose transporter type 1 (GLUT1) expression in the liver and also up-regulated GLUT4 and adiponectin expression in adipose tissue. The enhanced glucose uptake correlated with increased liver expression and elevated plasma levels of fibroblast growth factor 21 (FGF21), a hepatokine known to increase systemic insulin sensitivity and regulate whole-body lipid metabolism. Feeding LKO mice a triolein-supplemented but not tristearin-supplemented high-carbohydrate, low-fat diet reduced FGF21 expression and plasma levels. Consistently, SCD1 inhibition in primary hepatocytes induced FGF21 expression, which was repressed by treatment with oleate but not palmitoleate. Moreover, deletion of the transcriptional coactivator PPARγ coactivator 1α (PGC-1α) reduced hepatic and plasma FGF21 and white adipocyte tissue-specific GLUT4 expression and raised plasma glucose levels in LKO mice. These results suggest that hepatic oleate regulates glucose uptake in adipose tissue either directly or partially by modulating the hepatic PGC-1α-FGF21 axis.

Aljohani A ，Khan MI ，Bonneville A ，Guo C ，Jeffery J ，O'Neill L ，Syed DN ，Lewis SA ，Burhans M ，Mukhtar H ，Ntambi JM ... -  《-》

Barley sprout extracts reduce hepatic lipid accumulation in ethanol-fed mice by activating hepatic AMP-activated protein kinase.

Chronic alcohol consumption leads to hepatic lipid accumulation and alcoholic fatty liver disease. Previously, we demonstrated that barley sprout extract, which contains saponarin as an active compound, reduces hepatic steatosis. In this study, we investigated the effect of barley sprout extracts (BSE) on hepatic lipid accumulation in a mouse model of alcoholic fatty liver disease. Seven-week-old C57BL/6 mice were fed an alcohol-containing diet (5% ethanol) and a low or high dose of BSE (100 or 200mg/kg body weight, respectively) for 10days. The high dose of BSE significantly decreased hepatic lipid accumulation compared with the ethanol-only control group. In the second animal study, mice were fed an alcohol-containing diet for 10days, followed by a 45% high-fat diet with oral administration of BSE (100 or 200mg/day/kg body weight) for 4weeks. Mice in both BSE-fed groups showed reduced hepatic steatosis. In the livers of mice fed BSE, phosphorylation of AMP-activated protein kinase (AMPK) was increased, and expression of hepatic autophagy markers was elevated. In cultured hepatocytes, BSE (200μg/mL) increased the rate of fatty acid oxidation and reduced that of fatty acid synthesis. Taken together, these findings suggest that BSE promotes degradation of lipid droplets and subsequent activation of fat oxidation by activating AMPK in the liver, thus protecting against development of hepatic steatosis in alcohol-fed mice. Saponarin, a major flavonoid in BSE and an activator of AMPK, increased the activity of microsomal triglyceride transfer protein, which suggests that the reduction in hepatic triglyceride levels was mediated by this component of BSE. In conclusion, BSE ameliorated hepatic steatosis in a mouse model of ethanol-induced fatty liver by activating AMPK, an effect possibly mediated by the saponarin component.

Kim YJ ，Hwang SH ，Jia Y ，Seo WD ，Lee SJ ... -  《-》