“GLP-1 RAs may act directly on the hepatocytes. Transgenic rats deficient in dipeptidyl peptidase-4 (DPP4-), the enzyme that degrades endogenous GLP-1, have a threefold higher basal active GLP-1; they not only have lower hepatic fat, but are also protected against hepatic steatosis when fed a high-fat diet [8]. This reduced hepatic fat is mediated by down-regulation of transcription factors for enzymes involved in hepatic lipogenesis and up-regulation of carnitine palmitoyltransferase-1 (CPT1), a key regulator of fatty acid oxidation. Furthermore, in vitro studies suggest that the direct action of GLP-1 on hepatic steatosis is mediated by activation of key metabolic signalling pathways, including the AMP-activated protein kinase (AMPK) pathway and the insulin signalling pathway [8], [10], [11], which would be associated with increased hepatic fatty acid oxidation and hence improved insulin sensitivity. The recent identification of GLP1 receptors (GLP1-R) in human liver makes this mechanism a possibility [10].”
From: Improved Glycaemia Correlates with Liver Fat Reduction in Obese, Type 2 Diabetes, Patients Given Glucagon-Like Peptide-1 (GLP-1) Receptor Agonists
PLOS ONE, December 2012
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0050117
Effect of tirzepatide versus insulin degludec on liver fat content and abdominal adipose tissue in people with type 2 diabetes (SURPASS-3 MRI): a substudy of the randomised, open-label, parallel-group, phase 3 SURPASS-3 trial
The Lancet, April 2022
https://www.thelancet.com/journals/landia/article/PIIS2213-8587(22)00070-5/fulltext
“In post hoc analyses, higher tirzepatide doses significantly decreased NASH-related biomarkers and increased adiponectin in patients with T2DM.”
Effects of Novel Dual GIP and GLP-1 Receptor Agonist Tirzepatide on Biomarkers of Nonalcoholic Steatohepatitis in Patients With Type 2 Diabetes
Diabetes Care, April 2020
Tirzepatide adds hepatoprotection to its armoury
The Lancet, April 2022
https://www.thelancet.com/journals/landia/article/PIIS2213-8587(22)00074-2/fulltext
“Worldwide, metabolic dysfunction-associated fatty liver disease (MAFLD) is the most common chronic liver disease. MAFLD is associated with insulin resistance, type 2 diabetes mellitus (T2DM), obesity, hypertension, and dyslipidemia. Early diagnosis and management are vital to improving hepatic and cardiometabolic outcomes. Dietary change, weight loss, and structured exercise are the main treatment approaches for fatty liver disease. Since 2010, several investigational drug treatments failed to achieve regulatory approval due to mixed and unsatisfactory results. Although glucagon-like peptide 1 receptor agonists (GLP1-RAs) showed initial promise as therapeutic agents, metabolic liver damage can recur after monotherapy cessation. Dual incretin receptor agonists target the receptors for glucagon-like peptide 1 (GLP-1) and gastric inhibitory peptide (GIP). Importantly, on May 13, 2022, the US Food and Drug Administration (FDA) approved tirzepatide as the first dual GLP-1 and GIP receptor agonist for the treatment of T2DM. Dual incretin receptor agonists induce weight loss and enhance hepatic lipid metabolism and systemic insulin sensitivity. Insulin resistance and hepatic steatosis are the main contributors to the development of MAFLD. Treatment with dual incretin analogs reduces hepatic steatosis, lobular inflammation, liver cell damage, fibrosis, and total liver triglyceride levels. The availability of dual incretin receptor agonists for patients with MAFLD may result in weight control, normalizing insulin sensitivity, and reducing or even reversing metabolic dysfunction and liver damage. This Editorial aims to provide an update and discuss how treatment with dual incretin receptor agonists may maintain normal glucose levels and weight and control MAFLD.”
Editorial: Treatment with Dual Incretin Receptor Agonists to Maintain Normal Glucose Levels May Also Maintain Normal Weight and Control Metabolic Dysfunction-Associated Fatty Liver Disease (MAFLD)
Medical Science Monitor: International medical journal of experimental and clinical research, September 2022