Research Article Details
| Article ID: | A05397 |
| PMID: | 33271332 |
| Source: | Mol Metab |
| Title: | Hepatocyte-specific PKCβ deficiency protects against high-fat diet-induced nonalcoholic hepatic steatosis. |
| Abstract: | OBJECTIVE: Nonalcoholic hepatic steatosis, also known as fatty liver, is a uniform response of the liver to hyperlipidic-hypercaloric diet intake. However, the post-ingestive signals and mechanistic processes driving hepatic steatosis are not well understood. Emerging data demonstrate that protein kinase C beta (PKCβ), a lipid-sensitive kinase, plays a critical role in energy metabolism and adaptation to environmental and nutritional stimuli. Despite its powerful effect on glucose and lipid metabolism, knowledge of the physiological roles of hepatic PKCβ in energy homeostasis is limited. METHODS: The floxed-PKCβ and hepatocyte-specific PKCβ-deficient mouse models were generated to study the in vivo role of hepatocyte PKCβ on diet-induced hepatic steatosis, lipid metabolism, and mitochondrial function. RESULTS: We report that hepatocyte-specific PKCβ deficiency protects mice from development of hepatic steatosis induced by high-fat diet, without affecting body weight gain. This protection is associated with attenuation of SREBP-1c transactivation and improved hepatic mitochondrial respiratory chain. Lipidomic analysis identified significant increases in the critical mitochondrial inner membrane lipid, cardiolipin, in PKCβ-deficient livers compared to control. Moreover, hepatocyte PKCβ deficiency had no significant effect on either hepatic or whole-body insulin sensitivity supporting dissociation between hepatic steatosis and insulin resistance. CONCLUSIONS: The above data indicate that hepatocyte PKCβ is a key focus of dietary lipid perception and is essential for efficient storage of dietary lipids in liver largely through coordinating energy utilization and lipogenesis during post-prandial period. These results highlight the importance of hepatic PKCβ as a drug target for obesity-associated nonalcoholic hepatic steatosis. |
| DOI: | 10.1016/j.molmet.2020.101133 |
| Strategy ID | Therapy Strategy | Synonyms | Therapy Targets | Therapy Drugs | |
|---|---|---|---|---|---|
| S01 | Improve insulin resistance | insulin sensitizer; insulin resistance; glucose tolerance | Biguanide: increases 5-AMP activated protein kinase signaling; SGLT-2 inhibitor; Thiazalidinedione: selective PPAR-γ agonists; GLP-1 agonist | Metformin; Empagliflozin; Canagliflozin; Rosiglitazone; Pioglitazone; Liraglutide | Details |
| 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 |
| 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 |
| I14 | 9970 | Obesity | An overnutrition that is characterized by excess body fat, traditionally defined as an elevated ratio of weight to height (specifically 30 kilograms per meter squared), has_material_basis_in a multifactorial etiology related to excess nutrition intake, decreased caloric utilization, and genetic susceptibility, and possibly medications and certain disorders of metabolism, endocrine function, and mental illness. https://en.wikipedia.org/wiki/Obesity | disease of metabolism/acquired metabolic disease/ nutrition disease/overnutrition | Details |