Effect of Octreotide on Hepatic Steatosis in Diet-Induced Obesity in Rats

PLOS ONE, Dec 2019

Background Non-alcoholic fatty liver disease (NAFLD) caused by liver lipid dysregulation is linked to obesity. Somatostatin (SST) and its analogs have been used to treat pediatric hypothalamic obesity. However, the application of such drugs for the treatment of NAFLD has not been evaluated. Objective This study aimed to investigate the expression levels of important regulators of hepatic lipid metabolism and the possible effect of the SST analog octreotide on these regulators. Methods SD rats were assigned to a control group and a high-fat diet group. Obese rats from the high-fat diet group were further divided into the obese and octreotide-treated groups. The body weight, plasma SST, fasting plasma glucose (FPG), insulin, triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and free fatty acid (FFA) levels were measured. Hepatic steatosis was evaluated based on the liver TG content, HE staining and oil red O staining. The SREBP-1c, ACC1, FAS, MTP, apoB and ADRP expression levels in the liver were also determined by RT-PCR, qRT-PCR, western blot or ELISA. Results The obese rats induced by high-fat diet expressed more SREBP-1c, FAS and ADRP but less MTP protein in the liver than those of control rats, whereas octreotide intervention reversed these changes and increased the level of apoB protein. Compared to the control group, obese rats showed increased liver ACC1, SREBP-1c and apoB mRNA levels, whereas octreotide-treated rats showed decreased mRNA levels of apoB and SREBP-1c. This was accompanied by increased body weight, liver TG contents, FPG, TG, TC, LDL-C, FFA, insulin and derived homeostatic model assessment (HOMA) values. Octreotide intervention significantly decreased these parameters. Compared to the control group, the obese group showed a decreasing trend on plasma SST levels, which were significantly increased by the octreotide intervention. Conclusion Octreotide can ameliorate hepatic steatosis in obese rats, possibly by decreasing hepatic lipogenesis and increasing TG export from hepatocytes.

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Effect of Octreotide on Hepatic Steatosis in Diet-Induced Obesity in Rats

March Effect of Octreotide on Hepatic Steatosis in Diet-Induced Obesity in Rats Mao Li 0 1 2 Ting Ye 0 1 2 Xiao-Xia Wang 0 1 2 Xian Li 0 1 2 Ou Qiang 0 1 2 Tao Yu 0 1 2 Cheng-Wei Tang 0 2 Rui Liu 0 1 2 0 Current address: Department of Internal Medicine, Chongqing Emergency Medical Center, Chongqing Institution of Accident & Emergency Medicine , Chongqing , China 1 Division of Peptides Related to Human Disease, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University , Chengdu , China , 2 Department of Gastroenterology, West China Hospital, Sichuan University , Chengdu , China 2 Editor: Jonathan Peterson, East Tennessee State University , UNITED STATES - OPEN ACCESS Data Availability Statement: All relevant data are within the paper and its Supporting Information files. Funding: The project was supported by National Natural Science Foundation of China. The grant number was No. 30870919 and Rui Liu received the funding. Rui Liu had an important role in study design, decision to publish, and preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. Background Objective Methods Non-alcoholic fatty liver disease (NAFLD) caused by liver lipid dysregulation is linked to obesity. Somatostatin (SST) and its analogs have been used to treat pediatric hypothalamic obesity. However, the application of such drugs for the treatment of NAFLD has not been evaluated. This study aimed to investigate the expression levels of important regulators of hepatic lipid metabolism and the possible effect of the SST analog octreotide on these regulators. SD rats were assigned to a control group and a high-fat diet group. Obese rats from the high-fat diet group were further divided into the obese and octreotide-treated groups. The body weight, plasma SST, fasting plasma glucose (FPG), insulin, triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and free fatty acid (FFA) levels were measured. Hepatic steatosis was evaluated based on the liver TG content, HE staining and oil red O staining. The SREBP 1c, ACC1, FAS, MTP, apoB and ADRP expression levels in the liver were also determined by RT-PCR, qRT-PCR, western blot or ELISA. Results The obese rats induced by high-fat diet expressed more SREBP-1c, FAS and ADRP but less MTP protein in the liver than those of control rats, whereas octreotide intervention reversed these changes and increased the level of apoB protein. Compared to the control group, obese rats showed increased liver ACC1, SREBP-1c and apoB mRNA levels, whereas octreotide-treated rats showed decreased mRNA levels of apoB and SREBP-1c. This was accompanied by increased body weight, liver TG contents, FPG, TG, TC, LDL-C, FFA, insulin and derived homeostatic model assessment (HOMA) values. Octreotide intervention significantly decreased these parameters. Compared to the control group, the obese group showed a decreasing trend on plasma SST levels, which were significantly increased by the octreotide intervention. Conclusion Octreotide can ameliorate hepatic steatosis in obese rats, possibly by decreasing hepatic lipogenesis and increasing TG export from hepatocytes. Introduction Non-alcoholic fatty liver disease (NAFLD) is closely related to diabetes and obesity [ 1, 2 ] and has become a primary disease endangering public health. The incidence of NAFLD is reportedly 19.0% in the United States and as high as 44.3–56.6% in obese individuals with a BMI (body mass index) exceeding 35 kg/m2 [3]. NAFLD is manifested by the accumulation of lipids in the liver in the absence of excess alcohol consumption, caused by the imbalance between lipid input (fatty acid uptake and de novo lipogenesis) and output (VLDL export and fatty acid β-oxidation) [ 4 ]. Acetyl-CoA carboxylase (ACC1) and fatty acid synthase (FAS) are the regulatory enzymes for hepatic lipid synthesis. Insulin regulates the transcription and activation of liver sterol regulatory element binding protein-1c (SREBP-1c), which participates in liver fatty acid synthesis by stimulating the expression of ACC1 and FAS. Hyperactivation of SREBP-1c induces hepatic lipid accumulation [ 5, 6, 7 ], indicating that SREBP-1c-associated de novo lipogenesis is an important target of hepatic steatosis. For hepatic lipid export, triglyceride (TG) export depends not only on the secretion rate of VLDL but also on the TG content of VLDL. Microsomal triglyceride transfer protein (MTP) is a rate-limiting factor for the assembly of VLDL, which involves the transfer of a few lipids to apolipoprotein B (ApoB) [ 8, 9 ]. The esterification and maturation process of VLDL is associated with adipose differentiation-related protein (ADRP). ADRP can reduce the TG content of VLDL and promote fatty liver disease by diverting fatty acids from the VLDL assembly pathway into the production of cytosolic triglycerides [10]. Octre (...truncated)


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Mao Li, Ting Ye, Xiao-Xia Wang, Xian Li, Ou Qiang, Tao Yu, Cheng-Wei Tang, Rui Liu. Effect of Octreotide on Hepatic Steatosis in Diet-Induced Obesity in Rats, PLOS ONE, 2016, Volume 11, Issue 3, DOI: 10.1371/journal.pone.0152085