Research Article Details

Article ID: A02225
PMID: 34453940
Source: Life Sci
Title: Pancreastatin induces hepatic steatosis in type 2 diabetes by impeding mitochondrial functioning.
Abstract: AIMS: Mitochondrial dysfunction is among the key factors for the advancement of hepatic steatosis to NAFLD and NASH. Pancreastatin (PST: human ChgA250-301) is a dysglycemic hormone, previously reported to promote steatosis and inflammation in various animal models of metabolic disorders. Recently, we observed PST deregulates energy expenditure and mitochondrial functioning in perimenopausal rats. In the current study, we aimed to decipher the role of PST instigated altered mitochondrial functioning in hepatic steatosis. MAIN METHODS: The HepG2 cells were PST exposed and the Chga gene was knocked down using siRNA and lipofectamine. Parallelly, type 2 diabetes (T2D) was developed in C57BL/6 mice by HFD feeding and administered PST inhibitor (PSTi8). KEY FINDINGS: The PST exposed cells and HFD fed mice depicted: enhanced CHGA expression detected by IF/IHC, WB, and ELISA; dysregulated cellular ROS, mitochondrial ROS, oxygen consumption rate, mitochondrial membrane potential, ATP level, and NADP/NADP ratio; enhanced apoptosis determined by MTT, TUNEL, Annexin-V FITC, and WB of Bax/bcl2 and caspase 3; hepatic lipid accumulation upon Nile Red, Oil Red O, H&E staining, and the expression of SREBP-1c, FAS, ACC, and SCD; inflammation based on expression and circulatory level of IL6, IL-1β, and TNF-α. However, Chga knocked down HepG2 cells and PSTi8 treated mice unveiled protection from all the above abnormalities. SIGNIFICANCE: Collectively, the aforementioned data suggested the alteration in mitochondrial function induced by PST is responsible for hepatic steatosis in T2D.
DOI: 10.1016/j.lfs.2021.119905

Strategy ID Therapy Strategy Synonyms Therapy Targets Therapy Drugs
S02 Enhance lipid metabolism triglyceride-lowering; lipid tolerance; lipid metabolism 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) inhibitor; Decreases intestinal cholesterol absorption; FXR agonist; ACC inhibitor; FAS inhibitor; DGAT2 inhibitor; SCD-1 inhibitor Atorvastatin; Ezetimibe; Obeticholic Acid; GS-9674; GS-0976; TVB-2640; IONIS-DGAT2rx; Aramchol; Details
S13 Anti-apoptosis hepatocyte apoptosis; hepatic autophagy; apoptosis Pan-caspase inhibitor Emricasan Details

Target ID Target Name GENE Action Class UniProtKB ID Entry Name
T08 Tumor necrosis factor TNF inhibitor Cytokine P01375 TNFA_HUMAN Details
T10 Caspase-1 CASP1 inhibitor Enzyme P29466 CASP1_HUMAN Details
T18 Acetyl-CoA carboxylase 1 ACACA inhibitor Enzyme Q13085 ACACA_HUMAN Details
T20 Fatty acid synthase FASN inhibitor Enzyme P49327 FAS_HUMAN Details
T22 Stearoyl-CoA desaturase SCD inhibitor Enzyme O00767 SCD_HUMAN Details

Diseases ID DO ID Disease Name Definition Class
I05 9352 Type 2 diabetes mellitus A diabetes that is characterized by chronic hyperglycaemia with disturbances of carbohydrate, fat and protein metabolism resulting from defects in insulin secretion, insulin action, or both. A diabetes mellitus that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. http://en.wikipedia.org/wiki/Diabetes, http://en.wikipedia.org/wiki/Diabetes_mellitus_type_2 disease of metabolism/inherited metabolic disorder/ carbohydrate metabolic disorder/glucose metabolism disease/diabetes/ diabetes mellitus Details

Drug ID Drug Name Type DrugBank ID Targets Category Latest Progress
D328 Serine Chemical drug DB00133 SRR Improve insulin resistance Under clinical trials Details
D010 Amoxicillin Chemical drug DB01060 -- -- Under clinical trials Details
D579 Emfilermin Miscellany -- adipocytes Enhance lipid metabolism Under investigation Details
D589 Minor allele-specific small interfering RNA Miscellany -- PNPLA3-rs738409 (I148M) variant inhibitor -- Under investigation Details