Role of Lipid Droplet Proteins in the Development of NAFLD and Hepatic Insulin Resistance

Many studies have reported that metabolic dysfunction is closely involved in the complex mechanism underlying the development of non-alcoholic fatty liver disease (NAFLD), which has prompted a movement to consider renaming NAFLD as metabolic dysfunction-associated fatty liver disease (MAFLD). Metabolic dysfunction in this context encompasses obesity, type 2 diabetes mellitus, hypertension, dyslipidemia, and metabolic syndrome, with insulin resistance as the common underlying pathophysiology. Imbalance between energy intake and expenditure results in insulin resistance in various tissues and alteration of the gut microbiota, resulting in fat accumulation in the liver. The role of genetics has also been revealed in hepatic fat accumulation and fibrosis. In the process of fat accumulation in the liver, intracellular damage as well as hepatic insulin resistance further potentiates inflammation, fibrosis, and carcinogenesis. Increased lipogenic substrate supply from other tissues, hepatic zonation of Irs1, and other factors, including ER stress, play crucial roles in increased hepatic de novo lipogenesis in MAFLD with hepatic insulin resistance. Herein, we provide an overview of the factors contributing to and the role of systemic and local insulin resistance in the development and progression of MAFLD.

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Caloric Restriction Reverses Hepatic Insulin Resistance and Steatosis in Rats with Low Aerobic Capacity

Endocrinology ◽

10.1210/en.2010-0176 ◽

2010 ◽

Vol 151 (11) ◽

pp. 5157-5164 ◽

Cited By ~ 30

Author(s):

Thomas A. Bowman ◽

Sadeesh K. Ramakrishnan ◽

Meenakshi Kaw ◽

Sang Jun Lee ◽

Payal R. Patel ◽

...

Keyword(s):

Oxidative Stress ◽

Insulin Resistance ◽

Caloric Restriction ◽

Visceral Obesity ◽

Insulin Clearance ◽

Hepatic Insulin Resistance ◽

The Metabolic Syndrome ◽

Cell Adhesion Molecule 1 ◽

Muscle Triglyceride

Rats selectively bred for low aerobic running capacity exhibit the metabolic syndrome, including hyperinsulinemia, insulin resistance, visceral obesity, and dyslipidemia. They also exhibit features of nonalcoholic steatohepatitis, including chicken-wire fibrosis, inflammation, and oxidative stress. Hyperinsulinemia in these rats is associated with impaired hepatic insulin clearance. The current studies aimed to determine whether these metabolic abnormalities could be reversed by caloric restriction (CR). CR by 30% over a period of 2–3 months improved insulin clearance in parallel to inducing the protein content and activation of the carcinoembryonic antigen-related cell adhesion molecule 1, a main player in hepatic insulin extraction. It also reduced glucose and insulin intolerance and serum and tissue (liver and muscle) triglyceride levels. Additionally, CR reversed inflammation, oxidative stress, and fibrosis in liver. The data support a significant role of CR in the normalization of insulin and lipid metabolism in liver.

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Duration of rise in free fatty acids determines salicylate's effect on hepatic insulin sensitivity

Journal of Endocrinology ◽

10.1530/joe-12-0214 ◽

2013 ◽

Vol 217 (1) ◽

pp. 31-43 ◽

Cited By ~ 6

Author(s):

Sandra Pereira ◽

Wen Qin Yu ◽

María E Frigolet ◽

Jacqueline L Beaudry ◽

Yaniv Shpilberg ◽

...

Keyword(s):

Insulin Resistance ◽

Insulin Sensitivity ◽

Muscle Protein ◽

Hepatic Insulin Resistance ◽

Skeletal Muscle Protein ◽

Protein Levels ◽

Peripheral Insulin Resistance ◽

Plasma Ffa ◽

A Site

We have shown in rats that sodium salicylate (SS), which inhibits IkBa kinase B (IKKB), prevents hepatic and peripheral insulin resistance caused by short-term (7 h) i.v. administration of Intralipid and heparin (IH). We wished to further determine whether this beneficial effect of SS persisted after prolonged (48 h) IH infusion, which better mimics the chronic free fatty acid (FFA) elevation of obesity. Hence, we performed hyperinsulinemic euglycemic clamps with tritiated glucose methodology to determine hepatic and peripheral insulin sensitivity in rats infused with saline, IH, IH and SS, or SS alone. SS prevented peripheral insulin resistance (P<0.05) caused by prolonged plasma FFA elevation; however, it did not prevent hepatic insulin resistance. In skeletal muscle, protein levels of phospho-IkBa were augmented by prolonged IH administration and this was prevented by SS, suggesting that IH activates while SS prevents the activation of IKKB. Markers of IKKB activation, namely protein levels of phospho-IkBa and IkBa, indicated that IKKB is not activated in the liver after prolonged FFA elevation. Phosphorylation of serine 307 at insulin receptor substrate (IRS)-1, which is a marker of proximal insulin resistance, was not altered by IH administration in the liver, suggesting that this is not a site of hepatic insulin resistance in the prolonged lipid infusion model. Our results suggest that the role of IKKB in fat-induced insulin resistance is time and tissue dependent and that hepatic insulin resistance induced by prolonged lipid elevation is not due to an IRS-1 serine 307 kinase.

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Impact of PPAR-α induction on glucose homoeostasis in alcohol-fed mice

Clinical Science ◽

10.1042/cs20130064 ◽

2013 ◽

Vol 125 (11) ◽

pp. 501-511 ◽

Cited By ~ 11

Author(s):

Valérie Lebrun ◽

Olivier Molendi-Coste ◽

Nicolas Lanthier ◽

Christine Sempoux ◽

Patrice D. Cani ◽

...

Keyword(s):

Insulin Resistance ◽

Liver Disease ◽

Insulin Sensitivity ◽

Alcohol Consumption ◽

Insulin Signalling ◽

Liver Steatosis ◽

Hepatic Insulin Resistance ◽

Alcoholic Fatty Liver ◽

Glucose Homoeostasis

Alcohol consumption is a major cause of liver disease. It also associates with increased cardiovascular risk and Type 2 diabetes. ALD (alcoholic liver disease) and NAFLD (non-alcoholic fatty liver disease) share pathological features, pathogenic mechanisms and pattern of disease progression. In NAFLD, steatosis, lipotoxicity and liver inflammation participate to hepatic insulin resistance. The aim of the present study was to verify the effect of alcohol on hepatic insulin sensitivity and to evaluate the role of alcohol-induced steatosis and inflammation on glucose homoeostasis. C57BL/6J mice were fed for 20 days a modified Lieber–DeCarli diet in which the alcohol concentration was gradually increased up to 35% of daily caloric intake. OH (alcohol liquid diet)-fed mice had liver steatosis and inflammatory infiltration. In addition, these mice developed insulin resistance in the liver, but not in muscles, as demonstrated by euglycaemic–hyperinsulinaemic clamp and analysis of the insulin signalling cascade. Treatment with the PPAR-α (peroxisome-proliferator-activated receptor-α) agonist Wy14,643 protected against OH-induced steatosis and KC (Kupffer cell) activation and almost abolished OH-induced insulin resistance. As KC activation may modulate insulin sensitivity, we repeated the clamp studies in mice depleted in KC to decipher the role of macrophages. Depletion of KC using liposomes-encapsuled clodronate in OH-fed mice failed both to improve hepatic steatosis and to restore insulin sensitivity as assessed by clamp. Our study shows that chronic alcohol consumption induces steatosis, KC activation and hepatic insulin resistance in mice. PPAR-α agonist treatment that prevents steatosis and dampens hepatic inflammation also prevents alcohol-induced hepatic insulin resistance. However, KC depletion has little impact on OH-induced metabolic disturbances.

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High Glucose‐Aggravated Hepatic Insulin Resistance: Role of the NLRP3 Inflammasome in Kupffer Cells

Obesity ◽

10.1002/oby.22821 ◽

2020 ◽

Vol 28 (7) ◽

pp. 1270-1282

Author(s):

Tao Zheng ◽

Qibin Wang ◽

Yongcheng Dong ◽

Weidong Ma ◽

Yonghong Zhang ◽

...

Keyword(s):

Insulin Resistance ◽

Kupffer Cells ◽

Nlrp3 Inflammasome ◽

High Glucose ◽

Hepatic Insulin Resistance

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Role of Cannabinoid Receptor Type 1 in Insulin Resistance and Its Biological Implications

International Journal of Molecular Sciences ◽

10.3390/ijms20092109 ◽

2019 ◽

Vol 20 (9) ◽

pp. 2109 ◽

Cited By ~ 6

Author(s):

Arulkumar Nagappan ◽

Jooyeon Shin ◽

Myeong Ho Jung

Keyword(s):

Insulin Resistance ◽

Body Weight ◽

Insulin Sensitivity ◽

Hepatic Steatosis ◽

Cannabinoid Receptor ◽

Inflammatory Responses ◽

Hepatic Insulin Resistance ◽

Leptin Resistance ◽

Peripheral Tissues

Endogenous cannabinoids (ECs) are lipid-signaling molecules that specifically bind to cannabinoid receptor types 1 and 2 (CB1R and CB2R) and are highly expressed in central and many peripheral tissues under pathological conditions. Activation of hepatic CB1R is associated with obesity, insulin resistance, and impaired metabolic function, owing to increased energy intake and storage, impaired glucose and lipid metabolism, and enhanced oxidative stress and inflammatory responses. Additionally, blocking peripheral CB1R improves insulin sensitivity and glucose metabolism and also reduces hepatic steatosis and body weight in obese mice. Thus, targeting EC receptors, especially CB1R, may provide a potential therapeutic strategy against obesity and insulin resistance. There are many CB1R antagonists, including inverse agonists and natural compounds that target CB1R and can reduce body weight, adiposity, and hepatic steatosis, and those that improve insulin sensitivity and reverse leptin resistance. Recently, the use of CB1R antagonists was suspended due to adverse central effects, and this caused a major setback in the development of CB1R antagonists. Recent studies, however, have focused on development of antagonists lacking adverse effects. In this review, we detail the important role of CB1R in hepatic insulin resistance and the possible underlying mechanisms, and the therapeutic potential of CB1R targeting is also discussed.

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