Hepatic Stearoyl-CoA Desaturase (SCD)-1 Activity and Diacylglycerol but Not Ceramide Concentrations Are Increased in the Nonalcoholic Human Fatty Liver

Abstract

OBJECTIVE-To determine whether 1) hepatic ceramide and diacylglycerol concentrations, 2) SCD1 activity, and 3) hepatic lipogenic index are increased in the human nonalcoholic fatty liver.RESEARCH DESIGN AND METHODS-We studied 16 subjects with (n ϭ 8) and without (n ϭ 8) histologically determined nonalcoholic fatty liver (NAFL ϩ and NAFL Ϫ ) matched for age, sex, and BMI. Hepatic concentrations of lipids and fatty acids were quantitated using ultra-performance liquid chromatography coupled to mass spectrometry and gas chromatography. RESULTS-The absolute (nmol/mg) hepatic concentrations of diacylglycerols but not ceramides were increased in the NAFL ϩ group compared with the NAFL Ϫ group. The livers of the NAFL ϩ group contained proportionally less long-chain polyunsaturated fatty acids as compared with the NAFL Ϫ group. Liver fat percent was positively related to hepatic stearoyl-CoA desaturase 1 (SCD1) activity index (r ϭ 0.70, P ϭ 0.003) and the hepatic lipogenic index (r ϭ 0.54, P ϭ 0.030). Hepatic SCD1 activity index was positively related to the concentrations of diacylglycerols (r ϭ 0.71, P ϭ 0.002) but not ceramides (r ϭ 0.07, NS).CONCLUSIONS-We conclude that diacylglycerols but not ceramides are increased in NAFL. The human fatty liver is also characterized by depletion of long polyunsaturated fatty acids in the liver and increases in hepatic SCD1 and lipogenic activities. Diabetes 58: [203][204][205][206][207][208] 2009 N onalcoholic fatty liver disease (NAFLD) is characterized by lipid accumulation in the liver (Ն10% of liver weight), which cannot be attributed to alcohol consumption or any other liver disease (1). NAFLD covers a range from simple nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH) and fibrosis (1). The fatty liver is resistant to the action of insulin to inhibit hepatic glucose (2,3) and VLDL (4) production, resulting in hyperglycemia and hypertriglyceridemia. The mechanisms underlying insulin resistance in human NAFLD are unclear. While triacylglycerols themselves are inert, lipid intermediates may act as important regulators of both oxidative stress (5) and insulin signaling (6). In vitro studies as well as studies in animals suggest that diacylglycerols, which are immediate precursors of triacylglycerols (7), can induce insulin resistance by activating specific isoforms of protein kinase C (PKC) (8,9). The concentrations of diacylglycerols have recently been shown to be increased in human NAFLD compared with subjects with normal liver histology (10). Ceramides are another class of reactive lipids that mediate saturated fat-induced insulin resistance (6). There are no data comparing ceramide and diacylglycerol concentrations in the human liver or relating them to hepatic fat content.Sources of hepatic lipids include dietary chylomicron remnants, free fatty acids released from either adipose tissue triacylglycerols or chylomicrons hydrolyzed at a rate in excess of what can be taken up by tissues (spillover), and de novo lipogenesis (11). Increased lipolysis is a...

Circulating Triacylglycerol Signatures in Nonalcoholic Fatty Liver Disease Associated With the I148M Variant in PNPLA3 and With Obesity

“…Similar data were observed when liver fat was plotted against the splanchnic production rate of TAGs (47). TAGs containing saturated or monounsaturated fatty acids also predominate in liver biopsy samples of subjects with increased compared with normal liver fat content (49). Consistent with these data, the absolute serum concentrations of the abundant TAGs containing monounsaturated and saturated fatty acids were significantly increased in the obese group compared with the 'nonobese' group (Supplementary Table 2).…”

Hepatic Lipid Composition and Stearoyl-Coenzyme A Desaturase 1 mRNA Expression Can Be Estimated from Plasma VLDL Fatty Acid Ratios

“…Because the TG fraction contained significantly less stearate and polyunsaturated fatty acids (C20:3N6, C20:4N6, C22:6N3) and more oleate than the PL fraction, the indices of elongase, DNL, and SCD1 activity show strong differences between the hepatic lipid fractions. Such differences may have a major influence if total, unfractionated fatty acids are analyzed in tissue samples with different TG content (34 ). An increase in the triglyceride fraction would lead to a positive correlation between TG content and the desaturase and DNL indices as well as a negative correlation between TG content and elongase index and polyunsaturated fatty acid content solely due to the increasing proportion of TG-derived fatty acids.…”

From the metabolic syndrome to NAFLD or vice versa?

“…Hepatic gene expression of sterol regulatory element-binding protein (SREBP) 1c, key transcriptional activator of lipogenic genes, as well as of acetyl-CoA carboxylases (ACCs) and fatty acid synthase (FAS) have been shown to be increased in subjects with as compared to those without NAFLD [43]. Analyses of fatty acid composition revealed that the there is an excess of saturated fatty acids and saturated fatty acids -containing triglycerides in the human fatty liver [44]. In addition, the activity of a lipogenic enzyme stearoyl-CoA desaturase 1 (SCD1) is increased and the percentage of long polyunsaturated fatty acids decreased in subjects with as compared to those without NAFLD [44].…”

“…Analyses of fatty acid composition revealed that the there is an excess of saturated fatty acids and saturated fatty acids -containing triglycerides in the human fatty liver [44]. In addition, the activity of a lipogenic enzyme stearoyl-CoA desaturase 1 (SCD1) is increased and the percentage of long polyunsaturated fatty acids decreased in subjects with as compared to those without NAFLD [44]. This could decrease the ability of long polyunsaturated fatty acids to inhibit SREBP-1c activity [45] and [46].…”

“…We have recently shown that hepatic concentrations of diacylglycerols, the immediate precursors of triglycerides [47], but not of ceramides are directly related to hepatic fat content in the human liver [44]. Since both ceramides and diacylglycerols are able to cause insulin resistance by interfering with insulin signalling pathway [39] and [48], diacylglycerols rather than ceramides might contribute to hepatic insulin resistance in human NAFLD.…”