Methods and compositions using stearoyl-CoA desaturase to identify triglyceride reducing therapeutic agents

Abstract

The use of screening assays based on the role of human stearoyl-CoA desaturase-1 (“hSCD1”) in human diseases, disorders or conditions relating to serum levels of triglyceride, VLDL, HDL, LDL, total cholesterol, or production of secretions from mucous membranes, monounsaturated fatty acids, wax esters, and the like, is disclosed. Also disclosed are conventions useful in the prevention and/or treatment of such diseases.

1 - 119 . (canceled) 
     
     
         120 . A method for decreasing levels of triglyceride or VLDL in a human, comprising the step of inhibiting in said human a delta-9 stearoyl-CoA desaturase (SCD1) biological activity. 
     
     
         121 . The method of  claim 120 , wherein said inhibiting is due to administering to said human an inhibitor of the activity of human delta-9 stearoyl-CoA desaturase (SCD1) in an amount sufficient to reduce said SCD1 activity in said human. 
     
     
         122 . The method of  claim 121 , wherein said inhibitor does not substantially inhibit activity of delta-5 desaturase, delta-6 desaturase or fatty acid synthetase. 
     
     
         123 . The method of  claim 121 , wherein said inhibitor is administered in a form not complexed to Coenzyme A. 
     
     
         124 . A method for increasing HDL levels or decreasing LDL levels in a human, comprising the step of inhibiting in said human a delta-9 stearoyl-CoA desaturase (SCD1) biological activity. 
     
     
         125 . The method of  claim 124 , wherein said inhibiting is due to administering to said human an inhibitor of the activity of human delta-9 stearoyl-CoA desaturase (SCD1) in an amount sufficient to reduce said SCD1 activity in said human. 
     
     
         126 . The method of  claim 125 , wherein said inhibitor does not substantially inhibit activity of delta-5 desaturase, delta-6 desaturase or fatty acid synthetase. 
     
     
         127 . The method of  claim 125 , wherein said inhibitor is administered in a form not complexed to Coenzyme A. 
     
     
         128 . A method for treating a human afflicted with a disease or condition characterized by elevated serum triglyceride or VLDL, comprising the step of inhibiting in said human a delta-9 stearoyl-CoA desaturase (SCD1) biological activity. 
     
     
         129 . A method for treating a human afflicted with a disease or condition characterized by reduced serum HDL or increased serum LDL, comprising the step of inhibiting in said human a delta-9 stearoyl-CoA desaturase (SCD1) biological activity. 
     
     
         130 . The method of  claim 129 , wherein said inhibiting is due to administering to said patient an inhibitor of human delta-9 stearoyl-CoA desaturase (SCD1) activity in an amount sufficient to reduce said SCD1 activity in said human. 
     
     
         131 . The method of  claim 130 , wherein said inhibitor does not substantially inhibit activity of delta-5 desaturase, delta-6 desaturase or fatty acid synthetase. 
     
     
         132 . The method of  claim 130 , wherein said inhibitor is administered in a form not complexed to Coenzyme A. 
     
     
         133 . The method of  claim 129 , wherein said disease or condition is a member selected from the group consisting of cholesterol disorders, lipidemias, cardiovascular disease, diabetes, obesity, baldness, skin diseases, cancer and multiple sclerosis. 
     
     
         134 . The method of  claim 133 , wherein said disease or condition is Type II diabetes. 
     
     
         135 . The method of  claim 133 , wherein said disease or condition is obesity. 
     
     
         136 . The method of  claim 133 , wherein said disease or condition is cardiovascular disease. 
     
     
         137 . The method of  claim 136 , wherein said cardiovascular disease is coronary artery disease. 
     
     
         138 . The method of  claim 136 , wherein said cardiovascular disease is atherosclerosis. 
     
     
         139 . The method of  claim 130 , wherein the inhibitor is selected from the group consisting of a thia-fatty acid, a conjugated linoleic acid, and a cyclopropenoid fatty acid. 
     
     
         140 . The method of  claim 139 , wherein the thia-fatty acid is selected from the group consisting of a 9-thiastearic acid and a fatty acid having a sulfoxy moiety. 
     
     
         141 . The method of  claim 139 , wherein the conjugated linoleic acid is a trans-10, c is 12 conjugated linoleic acid. 
     
     
         142 . The method of  claim 139 , wherein the cyclopropenoid fatty acid is selected from the group consisting of sterulic acid and malvalic acid. 
     
     
         143 . The method of  claim 130 , wherein the inhibitor inhibits the transcription of an SCD1 gene. 
     
     
         144 . The method of  claim 130 , wherein the inhibitor is selected from the group consisting of a thiazoladinedione compound and a polyunsaturated fatty acid. 
     
     
         145 . The method of  claim 144 , wherein the thiazoladinedione compound is selected from the group consisting of BRL49653, Pioglitazone, Ciglitazone, Englitazone, and Troglitazone. 
     
     
         146 . The method of  claim 144 , wherein the polyunsaturated fatty acid is selected from the group consisting of dodecahexaenoic acid, arachidonic acid, and linoleic acid. 
     
     
         147 . The method of  claim 130 , wherein the inhibitor inhibits the SCD1 protein by inhibiting a protein selected from the group consisting of a cytochrome b 5  protein, a NADH-cytochrome b 5  reductase protein, and a terminal cyanide-sensitive desaturase protein. 
     
     
         148 . A method for treating a patient afflicted with a disease or condition related to total cholesterol or reverse cholesterol efflux, comprising the step of inhibiting in said human a delta-9 stearoyl-CoA desaturase (SCD1) biological activity. 
     
     
         149 . The method of  claim 148 , wherein said inhibiting is due to administering to said patient an inhibitor of human delta-9 stearoyl-CoA desaturase (SCD1) activity in an amount sufficient to reduce said SCD1 activity in said human. 
     
     
         150 . The method of  claim 149 , wherein said inhibitor does not substantially inhibit activity of delta-5 desaturase, delta-6 desaturase or fatty acid synthetase. 
     
     
         151 . The method of  claim 148 , wherein said inhibitor is administered in a form not complexed to Coenzyme A. 
     
     
         152 . The method of  claim 152 , wherein said disease or condition is a member selected from the group consisting of cholesterol disorders, lipidemias, cardiovascular disease, diabetes, obesity, cancer and multiple sclerosis. 
     
     
         153 . The method of  claim 152 , wherein said disease or condition is Type II diabetes. 
     
     
         154 . The method of  claim 152 , wherein said disease or condition is obesity. 
     
     
         155 . The method of  claim 152 , wherein said disease or condition is cardiovascular disease. 
     
     
         156 . The method of  claim 155 , wherein said cardiovascular disease is coronary artery disease. 
     
     
         157 . The method of  claim 155 , wherein said cardiovascular disease is atherosclerosis. 
     
     
         158 . The method of  claim 149 , wherein the inhibitor is selected from the group consisting of a thia-fatty acid, a conjugated linoleic acid, and a cyclopropenoid fatty acid. 
     
     
         159 . The method of  claim 158 , wherein the thia-fatty acid is selected from the group consisting of a 9-thiastearic acid and a fatty acid having a sulfoxy moiety. 
     
     
         160 . The method of  claim 158 , wherein the conjugated linoleic acid is a trans-10, cis 12 conjugated linoleic acid. 
     
     
         161 . The method of  claim 158 , wherein the cyclopropenoid fatty acid is selected from the group consisting of sterulic acid and malvalic acid. 
     
     
         162 . The method of  claim 149 , wherein the inhibitor inhibits the transcription of an SCD1 gene. 
     
     
         163 . The method of  claim 149 , wherein the inhibitor is selected from the group consisting of a thiazoladinedione compound and a polyunsaturated fatty acid. 
     
     
         164 . The method of  claim 163 , wherein the thiazoladinedione compound is selected from the group consisting of BRL49653, Pioglitazone, Ciglitazone, Englitazone, and Troglitazone. 
     
     
         165 . The method of  claim 163 , wherein the polyunsaturated fatty acid is selected from the group consisting of dodecahexaenoic acid, arachidonic acid, and linoleic acid. 
     
     
         166 . The method of  claim 149 , wherein the inhibitor inhibits the SCD1 protein by inhibiting a protein selected from the group consisting of a cytochrome b 5  protein, a NADH-cytochrome b 5  reductase protein, and a terminal cyanide-sensitive desaturase protein. 
     
     
         167 . A method for decreasing body mass index (BMI) in a human, comprising the step of inhibiting in said human a delta-9 stearoyl-CoA desaturase (SCD1) biological activity. 
     
     
         168 . The method of  claim 167 , wherein said inhibiting is due to administering to said human an inhibitor of a delta-9 stearoyl-CoA desaturase (SCD1) in an amount sufficient to reduce said SCD1 activity in said human. 
     
     
         169 . The method of  claim 168 , wherein said inhibitor does not substantially inhibit activity of delta-5 desaturase, delta-6 desaturase or fatty acid synthetase. 
     
     
         170 . The method of  claim 168 , wherein said inhibitor is administered in a form not complexed to Coenzyme A. 
     
     
         171 . The method of  claim 168 , wherein the inhibitor is selected from the group consisting of a thia-fatty acid, a conjugated linoleic acid, and a cyclopropenoid fatty acid. 
     
     
         172 . The method of  claim 171 , wherein the thia-fatty acid is selected from the group consisting of a 9-thiastearic acid and a fatty acid having a sulfoxy moiety. 
     
     
         173 . The method of  claim 171 , wherein the conjugated linoleic acid is a trans-10, c is 12 conjugated linoleic acid. 
     
     
         174 . The method of  claim 171 , wherein the cyclopropenoid fatty acid is selected from the group consisting of sterulic acid and malvalic acid. 
     
     
         175 . The method of  claim 168 , wherein the inhibitor inhibits the transcription of an SCD1 gene. 
     
     
         176 . The method of  claim 168 , wherein the inhibitor is selected from the group consisting of a thiazoladinedione compound and a polyunsaturated fatty acid. 
     
     
         177 . The method of  claim 176 , wherein the thiazoladinedione compound is selected from the group consisting of BRL49653, Pioglitazone, Ciglitazone, Englitazone, and Troglitazone. 
     
     
         178 . The method of  claim 176 , wherein the polyunsaturated fatty acid is selected from the group consisting of dodecahexaenoic acid, arachidonic acid, and linoleic acid. 
     
     
         179 . The method of  claim 168 , wherein the inhibitor inhibits the SCD1 protein by inhibiting a protein selected from the group consisting of a cytochrome b 5  protein, a NADH-cytochrome b 5  reductase protein, and a terminal cyanide-sensitive desaturase protein.