Targeting protein modifications in metabolic diseases: molecular mechanisms and targeted therapies

Abstract

The ever-increasing prevalence of noncommunicable diseases (NCDs) represents a major public health burden worldwide. The most common form of NCD is metabolic diseases, which affect people of all ages and usually manifest their pathobiology through life-threatening cardiovascular complications. A comprehensive understanding of the pathobiology of metabolic diseases will generate novel targets for improved therapies across the common metabolic spectrum. Protein posttranslational modification (PTM) is an important term that refers to biochemical modification of specific amino acid residues in target proteins, which immensely increases the functional diversity of the proteome. The range of PTMs includes phosphorylation, acetylation, methylation, ubiquitination, SUMOylation, neddylation, glycosylation, palmitoylation, myristoylation, prenylation, cholesterylation, glutathionylation, S-nitrosylation, sulfhydration, citrullination, ADP ribosylation, and several novel PTMs. Here, we offer a comprehensive review of PTMs and their roles in common metabolic diseases and pathological consequences, including diabetes, obesity, fatty liver diseases, hyperlipidemia, and atherosclerosis. Building upon this framework, we afford a through description of proteins and pathways involved in metabolic diseases by focusing on PTM-based protein modifications, showcase the pharmaceutical intervention of PTMs in preclinical studies and clinical trials, and offer future perspectives. Fundamental research defining the mechanisms whereby PTMs of proteins regulate metabolic diseases will open new avenues for therapeutic intervention.

The relationship between folic acid and nonalcoholic fatty liver disease

“…Many studies have confirmed DNA methylation changed in liver biopsy of patients with NAFLD 45,[47][48][49][50][51][52][53][54][55][56][57][58][59][60][61][62][63][64][65] (Figure 3). A recent investigation revealed a marked reduction in global DNA methylation among 47 individuals diagnosed with NAFLD compared to a cohort of 18 lean subjects without NAFLD, as assessed via liver biopsy.…”

Regulation of insulin secretion by the post-translational modifications

“…Moreover, several drug candidates for T2DM have been proved to regulate protein PTMs. For example, Glucokinase activators (GKAs), including dorzagliatin, MK-0941 and AZD1656, also promotes SUMOylation of pancreatic glucokinase, (Wu et al, 2023), implying PTM can be the potential drug targets for T2DM. Thus, further in-depth studies of PTMs in insulin secretion are in need.…”

Post-Translational Modifications and Diabetes

“…Diabetes-induced histone PTMs have profound consequences in the pathology of diabetic complications [ 40 ]. Decreased expression of glucose transporter GLUT4, encoded by Slc2a4 gene, in the skeletal muscle of T1D- and T2D-like animals has been detected [ 32 ].…”