MC-LR Aggravates Liver Lipid Metabolism Disorders in Obese Mice Fed a High-Fat Diet via PI3K/AKT/mTOR/SREBP1 Signaling Pathway

Abstract

Obesity, a metabolic disease caused by excessive fat accumulation in the body, has attracted worldwide attention. Microcystin-LR (MC-LR) is a hepatotoxic cyanotoxin which has been reportedly to cause lipid metabolism disorder. In this study, C57BL/6J mice were fed a high-fat diet (HFD) for eight weeks to build obese an animal model, and subsequently, the obese mice were fed MC-LR for another eight weeks, and we aimed to determine how MC-LR exposure affects the liver lipid metabolism in high-fat-diet-induced obese mice. The results show that MC-LR increased the obese mice serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT), indicating damaged liver function. The lipid parameters include serum triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-c), and liver TG, which were all increased, whilst the high-density lipoprotein cholesterol (HDL-c) was decreased. Furthermore, after MC-LR treatment, histopathological observation revealed that the number of red lipid droplets increased, and that steatosis was more severe in the obese mice. In addition, the lipid synthesis-related genes were increased and the fatty acid β-oxidation-related genes were decreased in the obese mice after MC-LR exposure. Meanwhile, the protein expression levels of phosphorylation phosphatidylinositol 3-kinase (p-PI3K), phosphorylation protein kinase B (p-AKT), phosphorylation mammalian target of rapamycin (p-mTOR), and sterol regulatory element binding protein 1c (SREBP1-c) were increased; similarly, the p-PI3K/PI3K, p-AKT/AKT, p-mTOR/mTOR, and SREBP1/β-actin were significantly up-regulated in obese mice after being exposed to MC-LR, and the activated PI3K/AKT/mTOR/SREBP1 signaling pathway. In addition, MC-LR exposure reduced the activity of superoxide dismutase (SOD) and increased the level of malondialdehyde (MDA) in the obese mice’s serum. In summary, the MC-LR could aggravate the HFD-induced obese mice liver lipid metabolism disorder by activating the PI3K/AKT/mTOR/SREBP1 signaling pathway to hepatocytes, increasing the SREBP1-c-regulated key enzymes for lipid synthesis, and blocking fatty acid β-oxidation.

Subchronic Microcystin-LR Aggravates Colorectal Inflammatory Response and Barrier Disruption via Raf/ERK Signaling Pathway in Obese Mice

“…We use the same animal model as that from our previous study and the results are consistent with this study [28]. For the duration of the exposure, the body weights of the mice were measured every 2 weeks.…”

“…Su et al also discovered that MC-LR extended blood stool duration, exacerbated colonic mucosa ulcer, and reduced colon length in mice with DSS-induced colitis [31]. For MC-LR-induced organ damage in a poor dietary environment, only the study by Arman et al and Chu et al found that MC-LR exposure causes more severe HFHC/HFD-induced NAFLD and kidney damage [20,21,28]. Our data indicate for the first time that MC-LR exposure increases colorectal damage in the HFD-treatment group.…”

Integrated 16s RNA sequencing and network pharmacology to explore the effects of polyphenol-rich raspberry leaf extract on weight control

“…Obesity is one of the major public health problems worldwide, and long-term intake of HFD can lead to fat accumulation, metabolic disorders, and an increased risk of obesity ( 3 ). Compared to drugs that can produce certain side effects, dietary intervention with natural diets rich in polyphenols can be a promising means of treating obesity.…”

“…The World Health Organization (WHO) defines both overweight (a body mass index (BMI) ≥ 25 kg/m 2 ) and obesity (BMI ≥ 30 kg/m 2 ) as an abnormal or excessive fat accumulation ( 1 ). Obesity greatly increases the risk of diseases including type 2 diabetes, fatty liver, hyperglycemia and coronary heart disease, as well as reduces quality of life and life expectancy ( 2 , 3 ). Since 1980, the frequency of overweight and obese individuals has doubled, hence, obesity has become a growing public health problem ( 1 ).…”

Phytoformulation with hydroxycitric acid and capsaicin protects against high-fat-diet-induced obesity cardiomyopathy by reducing cardiac lipid deposition and ameliorating inflammation and apoptosis in the heart

“… 9 From a biochemical perspective, a HFD may provoke the body's inflammatory response, 10 cause a mismatch between energy intake and consumption, release free fatty acids into the blood, and lead to a disorder of lipid metabolism. 11 …”