incretins and Liver-Neoplasms

The prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing worldwide. In some patients with NAFLD, isolated steatosis can progress to advanced stages with non-alcoholic steatohepatitis (NASH) and fibrosis, increasing the risk of cirrhosis and hepatocellular carcinoma. Furthermore, NAFLD is believed to be involved in the pathogenesis of common disorders such as type 2 diabetes and cardiovascular disease. In this Review, we highlight novel concepts related to diagnosis, risk prediction, and treatment of NAFLD. First, because NAFLD is a heterogeneous disease, the advanced stages of which seem to be strongly affected by comorbidities such as insulin resistance and type 2 diabetes, early use of reliable, non-invasive diagnostic tools is needed, particularly in patients with insulin resistance or diabetes, to allow the identification of patients at different disease stages. Second, although the strongest genetic risk alleles for NAFLD (ie, the 148Met allele in PNPLA3 and the 167Lys allele in TM6SF2) are associated with increased liver fat content and progression to NASH and cirrhosis, these alleles are also unexpectedly associated with an apparent protection from cardiovascular disease. If consistent across diverse populations, this discordance in NAFLD-related risk prediction between hepatic and extrahepatic disease might need to be accounted for in the management of NAFLD. Third, drug treatments assessed in NAFLD seem to differ with respect to cardiometabolic and antifibrotic efficacy, suggesting the need to better identify and tailor the most appropriate treatment approach, or to use a combination of approaches. These emerging concepts could contribute to the development of a multidisciplinary approach for endocrinologists and hepatologists working together in the management of NAFLD.

Topics: Antioxidants; Bariatric Surgery; Carcinoma, Hepatocellular; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Disease Progression; Dysbiosis; Gastrointestinal Microbiome; Genetic Predisposition to Disease; Humans; Incretins; Insulin Resistance; Lipase; Liver Cirrhosis; Liver Neoplasms; Membrane Proteins; Non-alcoholic Fatty Liver Disease; Obesity, Abdominal; Risk Assessment; Risk Reduction Behavior; Sodium-Glucose Transporter 2 Inhibitors

Nonalcoholic-fatty-liver-disease/nonalcoholic steatohepatitis (NAFLD/NASH) is expected to become the leading liver disease worldwide. Typical liver-related complications are fibrosis, cirrhosis, and the development of hepatocellular cancer (HCC) with the need for liver transplantation. Up to now there is no approved pharmacotherapy. Indeed, this might be due to the complexity of this disease. While the cheapest therapeutic approach is still a lifestyle change leading to weight loss, the proportion of people achieving sufficient weight reduction without additional support is low. Newly developed drugs are expensive and lack a breakthrough in therapeutic success. One reason might be that drugs developed often derive from murine models. Unfortunately, there is little overlap between genes in human and mice that are responsible for the development of NAFLD/NASH. This review aims at summarizing latest developments as well as stress again that more translational research is necessary.. Therapy of NAFLD/NASH is easy and very complex at the same time, as the current main target is weight reduction. Since this is in fact not easily achieved and maintained by many affected individuals, pharmacotherapy to halt the progression of NAFLD/NASH is urgently warranted. More translational studies are needed to understand the metabolic mechanisms and interactions between the liver, gut, oxidative stress and the processes leading to NAFLD progression and HCC development, even in the absence of cirrhosis.

Topics: Animals; Bariatric Surgery; Disease Models, Animal; Disease Progression; Drug Evaluation, Preclinical; Humans; Hypolipidemic Agents; Incretins; Life Style; Lipogenesis; Liver; Liver Cirrhosis; Liver Neoplasms; Mice; Non-alcoholic Fatty Liver Disease; Obesity; Oxidative Stress; Species Specificity; Translational Research, Biomedical; Weight Loss; Weight Reduction Programs

Dipeptidyl peptidase-4 (DPP-4) is a membrane-associated peptidase, also known as CD26. DPP-4 has widespread organ distribution throughout the body and exerts pleiotropic effects via its peptidase activity. A representative target peptide is glucagon-like peptide-1, and inactivation of glucagon-like peptide-1 results in the development of glucose intolerance/diabetes mellitus and hepatic steatosis. In addition to its peptidase activity, DPP-4 is known to be associated with immune stimulation, binding to and degradation of extracellular matrix, resistance to anti-cancer agents, and lipid accumulation. The liver expresses DPP-4 to a high degree, and recent accumulating data suggest that DPP-4 is involved in the development of various chronic liver diseases such as hepatitis C virus infection, non-alcoholic fatty liver disease, and hepatocellular carcinoma. Furthermore, DPP-4 occurs in hepatic stem cells and plays a crucial role in hepatic regeneration. In this review, we described the tissue distribution and various biological effects of DPP-4. Then, we discussed the impact of DPP-4 in chronic liver disease and the possible therapeutic effects of a DPP-4 inhibitor.

Topics: Carcinoma, Hepatocellular; Dipeptidyl Peptidase 4; End Stage Liver Disease; Extracellular Matrix; Fatty Liver; Gene Expression Regulation, Enzymologic; Hepatitis C; Humans; Incretins; Insulin Resistance; Lipid Metabolism; Liver Neoplasms; Non-alcoholic Fatty Liver Disease