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PS-341 alleviates chronic low-grade inflammation and improves insulin sensitivity through the inhibition of TM4 (UBAC2) degradation
- Source :
- Nutrition & Metabolism, Nutrition & Metabolism, Vol 18, Iss 1, Pp 1-10 (2021)
- Publication Year :
- 2021
-
Abstract
- Background The TM4 (UBAC2) protein, which contains 4 transmembrane domains and one ubiquitin binding domain, is mainly expressed in cell and nuclear membranes. The current research aimed to explore the role of TM4 in metabolic inflammation and to examine whether the ubiquitin–proteasome inhibitor PS-341 could regulate the function of TM4. Methods The metabolic phenotypes of TM4 knockout (KO) mice were studied. We next explored the association between the polymorphisms of TM4 and obesity in a Chinese Han population. TM4 expression in the visceral fat of obese patients who underwent laparoscopic cholecystectomy was also analysed. Finally, the effect of PS-341 on the degradation and function of the TM4 protein was investigated in vivo and in vitro. Results TM4 KO mice developed obesity, hepatosteatosis, hypertension, and glucose intolerance under a high-fat diet. TM4 counterregulated Nur77, IKKβ, and NF-kB both in vivo and in vitro. The TM4 SNP rs147851454 is significantly associated with obesity after adjusting for age and sex (OR 1.606, 95% CI 1.065–2.422 P = 0.023) in 3394 non-diabetic and 1862 type 2 diabetic adults of Han Chinese. TM4 was significantly downregulated in the visceral fat of obese patients. PS-341 induced TM4 expression through inhibition of TM4 degradation in vitro. In db/db mice, PS-341 administration led to downregulation of Nur77/IKKβ/NF-κB expression in visceral fat and liver, and alleviation of hyperglycaemia, hypertension, and glucose intolerance. The hyperinsulinaemic-euglycaemic clamp demonstrated that PS-341 improved the glucose infusion rate and alleviated insulin resistance in db/db mice. Conclusions PS-341 alleviates chronic low-grade inflammation and improves insulin sensitivity through inhibition of TM4 degradation.
- Subjects :
- UBAC2
medicine.medical_specialty
RC620-627
Nerve growth factor IB
Ubiquitin binding
Endocrinology, Diabetes and Metabolism
Medicine (miscellaneous)
Inflammation
Clinical nutrition
03 medical and health sciences
0302 clinical medicine
Insulin resistance
Downregulation and upregulation
In vivo
Internal medicine
Medicine
TX341-641
Obesity
Nutritional diseases. Deficiency diseases
030304 developmental biology
0303 health sciences
Nutrition and Dietetics
business.industry
Nutrition. Foods and food supply
Research
medicine.disease
PS-341
Metabolic inflammation
Endocrinology
030220 oncology & carcinogenesis
medicine.symptom
business
Subjects
Details
- ISSN :
- 17437075 and 14785145
- Volume :
- 18
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- Nutritionmetabolism
- Accession number :
- edsair.doi.dedup.....345a333aee9da40d0b3712cd12c0e136