Hepatic microRNA miR-182-5p Links Type 2 Diabetes and Fatty Liver Disease in Obesity

Core Concepts

Upregulation of hepatic miR-182-5p in obese type 2 diabetic individuals represses the expression of the metabolic regulator LRP6, leading to impaired glucose homeostasis and increased hepatic lipogenesis.

Abstract

The study aimed to comprehensively profile the hepatic microRNA (miRNA) transcriptome in obese individuals with and without type 2 diabetes (T2D) and to identify miRNAs that contribute to the development of T2D-associated metabolic dysregulations.
Key findings:

The authors identified a distinct signature of 28 hepatic miRNAs that were differentially expressed in obese T2D individuals compared to obese non-diabetic controls.
Among these, the human-murine conserved miRNA miR-182-5p showed the strongest upregulation in T2D and was associated with multiple metabolic traits, including fasting glucose, HbA1c, and liver fat content.
The miR-182-5p target gene LRP6, a Wnt co-receptor crucial for regulating glucose and lipid metabolism, was consistently downregulated in livers of obese T2D humans and mice.
Mechanistically, overexpression of miR-182-5p in hepatic cells and mice reduced LRP6 expression, impaired glucose uptake and insulin signaling, and increased hepatic triglyceride content.
The induction of hepatic miR-182-5p in obesity required chronic metabolic stress, as it was only observed after long-term high-fat diet feeding in mice. Weight loss reversed the upregulation of miR-182-5p and partially restored its target genes.
These findings establish hepatic miR-182-5p as a key regulator linking type 2 diabetes and non-alcoholic fatty liver disease in obesity, and highlight its potential as a therapeutic target.

Stats

Hepatic miR-182-5p expression was 2.3-fold upregulated in obese type 2 diabetic individuals compared to obese non-diabetic controls.
Overexpression of miR-182-5p in mice increased hepatic triglyceride content by 2.19-fold and fasting insulin levels by 2.25-fold.

Quotes

"Upregulation of hsa-miR-182-5p in human obese diabetic liver simultaneously decreases the metabolic pathways of beta oxidation and stimulates lipogenesis."
"Loss of LRP6 mediated activation of the Wnt/beta-catenin signaling pathway enhances hepatic lipid accumulation by increasing de novo lipogenesis and triglyceride synthesis."

Key Insights Distilled From

Liver microRNA transcriptome reveals miR-182 as link between type 2 diabetes and fatty liver disease in obesity

by Krause,C., B... at www.biorxiv.org 10-04-2023

https://www.biorxiv.org/content/10.1101/2023.10.02.560594v2

Deeper Inquiries

How do genetic and environmental factors interact to regulate hepatic miR-182-5p expression in obesity and type 2 diabetes?

In the context of obesity and type 2 diabetes, the regulation of hepatic miR-182-5p expression is influenced by a complex interplay of genetic and environmental factors. Genetic factors play a significant role in determining the baseline expression levels of miR-182-5p. Variations in the DNA sequence, such as single nucleotide polymorphisms (SNPs) in the miR-182-5p gene or its regulatory regions, can impact the transcription and processing of miR-182-5p. These genetic variations can predispose individuals to altered miR-182-5p expression levels, potentially increasing the risk of developing metabolic disorders like obesity and type 2 diabetes.
Environmental factors, such as diet and lifestyle, also play a crucial role in regulating hepatic miR-182-5p expression. High-fat diets, which are commonly associated with obesity, have been shown to upregulate miR-182-5p expression in the liver. Chronic exposure to a high-fat diet can induce epigenetic changes in the liver, leading to dysregulation of miRNA expression patterns, including miR-182-5p. Additionally, factors like physical inactivity, stress, and exposure to environmental toxins can further modulate miR-182-5p expression in the liver.
The interaction between genetic and environmental factors is dynamic and bidirectional. Genetic predispositions can influence how individuals respond to environmental stimuli, such as diet and lifestyle choices, leading to differential regulation of miR-182-5p expression. Conversely, environmental factors can also impact the expression of genes involved in the miR-182-5p regulatory network, creating a feedback loop that contributes to the development and progression of obesity and type 2 diabetes.

What are the potential therapeutic implications of targeting the miR-182-5p/LRP6 axis for the treatment of non-alcoholic fatty liver disease in type 2 diabetic patients?

Targeting the miR-182-5p/LRP6 axis holds significant therapeutic potential for the treatment of non-alcoholic fatty liver disease (NAFLD) in type 2 diabetic patients. The dysregulation of miR-182-5p and its target gene LRP6 plays a critical role in the pathogenesis of NAFLD by promoting hepatic lipid accumulation and impairing glucose homeostasis. By targeting this axis, several therapeutic implications can be realized:

Reducing Hepatic Lipid Accumulation: Inhibiting miR-182-5p or restoring LRP6 expression can help reduce hepatic de novo lipogenesis and triglyceride synthesis, thereby mitigating liver fat accumulation in NAFLD patients.

Improving Insulin Sensitivity: Restoring LRP6 expression can enhance insulin signaling pathways in the liver, leading to improved glucose uptake and utilization. This can help address insulin resistance, a common feature of type 2 diabetes and NAFLD.

Preventing Disease Progression: Targeting the miR-182-5p/LRP6 axis can potentially halt or slow down the progression of NAFLD to more severe stages, such as non-alcoholic steatohepatitis (NASH) or liver fibrosis, by regulating key metabolic pathways involved in liver health.

Personalized Therapies: Understanding the genetic and environmental factors that influence miR-182-5p expression can enable the development of personalized therapies that target specific molecular pathways based on individual patient profiles.

Overall, targeting the miR-182-5p/LRP6 axis offers a promising approach for the treatment of NAFLD in type 2 diabetic patients by addressing the underlying mechanisms that drive hepatic lipid accumulation and insulin resistance.

What other metabolic pathways and organ systems might be influenced by the dysregulation of hepatic miR-182-5p in the context of obesity and type 2 diabetes?

The dysregulation of hepatic miR-182-5p in the context of obesity and type 2 diabetes can have broad implications for various metabolic pathways and organ systems beyond the liver. Some of the key metabolic pathways and organ systems that might be influenced by the dysregulation of miR-182-5p include:

Adipose Tissue: Dysregulation of miR-182-5p can impact adipose tissue metabolism by altering adipocyte differentiation, lipid storage, and adipokine secretion. This can contribute to the development of obesity and insulin resistance.

Pancreas: Changes in miR-182-5p expression can affect pancreatic beta cell function and insulin secretion, potentially exacerbating the progression of type 2 diabetes by impairing glucose-stimulated insulin release.

Muscle Tissue: Altered miR-182-5p levels can influence muscle metabolism, affecting glucose uptake, glycogen storage, and energy expenditure. This can contribute to insulin resistance and impaired muscle function in obese and diabetic individuals.

Gut Microbiota: The dysregulation of miR-182-5p in the liver can impact gut microbiota composition and function, leading to alterations in nutrient absorption, inflammation, and metabolic homeostasis.

Cardiovascular System: Changes in miR-182-5p expression can affect cardiovascular health by influencing lipid metabolism, vascular function, and inflammation, increasing the risk of cardiovascular complications in obese and diabetic patients.

Central Nervous System: Dysregulation of miR-182-5p may impact central regulation of energy balance, appetite control, and metabolic homeostasis through its effects on hypothalamic and brainstem circuits involved in the regulation of food intake and energy expenditure.

By influencing these interconnected metabolic pathways and organ systems, hepatic miR-182-5p dysregulation can have systemic effects on whole-body metabolism, contributing to the pathogenesis of obesity and type 2 diabetes and their associated complications.