Role of Obesity and Lipotoxicity in the Development of Nonalcoholic Steatohepatitis: Pathophysiology and Clinical Implications

doi:10.1053/j.gastro.2012.02.003

Gastroenterology

Volume 142, Issue 4, April 2012, Pages 711-725.e6

https://doi.org/10.1053/j.gastro.2012.02.003 Get rights and content

As obesity reaches epidemic proportions, nonalcoholic fatty liver disease (NAFLD) is becoming a frequent cause of patient referral to gastroenterologists. There is a close link between dysfunctional adipose tissue in NAFLD and common conditions such as metabolic syndrome, type 2 diabetes mellitus, and cardiovascular disease. This review focuses on the pathophysiology of interactions between adipose tissue and target organs in obesity and the resulting clinical implications for the management of nonalcoholic steatohepatitis. The release of fatty acids from dysfunctional and insulin-resistant adipocytes results in lipotoxicity, caused by the accumulation of triglyceride-derived toxic metabolites in ectopic tissues (liver, muscle, pancreatic beta cells) and subsequent activation of inflammatory pathways, cellular dysfunction, and lipoapoptosis. The cross talk between dysfunctional adipocytes and the liver involves multiple cell populations, including macrophages and other immune cells, that in concert promote the development of lipotoxic liver disease, a term that more accurately describes the pathophysiology of nonalcoholic steatohepatitis. At the clinical level, adipose tissue insulin resistance contributes to type 2 diabetes mellitus and cardiovascular disease. Treatments that rescue the liver from lipotoxicity by restoring adipose tissue insulin sensitivity (eg, significant weight loss, exercise, thiazolidinediones) or preventing activation of inflammatory pathways and oxidative stress (ie, vitamin E, thiazolidinediones) hold promise in the treatment of NAFLD, although their long-term safety and efficacy remain to be established. Better understanding of pathways that link dysregulated adipose tissue, metabolic dysfunction, and liver lipotoxicity will result in improvements in the clinical management of these challenging patients.

Section snippets

Adipose Tissue Adaptation in Obesity

Normal adipocyte function depends on a number of factors, such as adipocyte number, size, the overall hormonal milieu, and interaction with other cell types within the adipose tissue bed.¹⁵ Fat cells derive from multipotent mesenchymal stem cells that develop into adipoblasts and then to preadipose cells (lipid-depleted precursors of the future adult white adipocyte). Maturation depends on a complex signal system. Up-regulation by peroxisome proliferator-activated receptor γ (PPAR-γ) is

Clinical Impact of Adipose Tissue Dysfunction and Lipotoxicity

The prior section has set the stage for understanding the clinical impact of excess fatty acids across a variety of tissues and the role of obesity in NAFLD.

Lifestyle Intervention

It is well established that lifestyle interventions that result in weight loss decrease CVD¹⁹⁶ and delay the development of T2DM.¹⁹⁷ However, large long-term trials are yet unavailable in NAFLD, so the most effective lifestyle intervention remains unclear because studies have been usually small and uncontrolled and included diverse diets and exercise programs.198, 199, 200, 201

Weight loss improves liver aminotransferase levels and hepatic steatosis when measured either by ultrasonography or MRS

Future Directions

It is likely that improved patient care will result from an increased awareness among clinicians of the close link between obesity-induced lipotoxicity and NAFLD, T2DM, and CVD. As previously suggested,²⁵⁴ it may help the clinician to call this condition “lipotoxic liver disease,” a reminder of the nature of the disease and much more descriptive than “not being alcoholic steatohepatitis” (NASH). Future work needs to deepen our understanding of the cross talk between liver and adipose tissue

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Reviews and PerspectivesReviews in Basic and Clinical Gastroenterology and HepatologyRole of Obesity and Lipotoxicity in the Development of Nonalcoholic Steatohepatitis: Pathophysiology and Clinical Implications

Section snippets

Adipose Tissue Adaptation in Obesity

Clinical Impact of Adipose Tissue Dysfunction and Lipotoxicity

Lifestyle Intervention

Future Directions

Lancet

Am J Med

Lancet

Trends Endocrinol Metab

J Biol Chem

J Lipid Res

Lancet

Endocrinol Metab Clin North Am

J Lipid Res

J Lipid Res

Cell Metab

Trends Endocrinol Metab

Hepatology

Am J Pathol

Gastroenterology

Variations in BMI and prevalence of health risks in diverse racial and ethnic populations

Obesity

Identification and characterization of metabolically benign obesity in humans

Arch Intern Med

Effect of adipose tissue insulin resistance on metabolic parameters and liver histology in obese patients with NAFLD

Hepatology

Obesity - United States, 1988-2008

MMWR Surveill Summ

Prevalence and trends in obesity among US adults, 1999-2008

JAMA

Obesity in adulthood and its consequences for life expectancy: a life-table analysis

Ann Intern Med

Poverty and obesity in the U.S

Diabetes

The role of adipose tissue and lipotoxicity in the pathogenesis of type 2 diabetes

Curr Diab Rep

Role of low energy expenditure and sitting in obesity, metabolic syndrome, type 2 diabetes, and cardiovascular disease

Diabetes

Health care utilization and costs by metabolic syndrome risk factors

Metab Syndr Relat Disord

Reviews and Perspectives
Reviews in Basic and Clinical Gastroenterology and Hepatology
Role of Obesity and Lipotoxicity in the Development of Nonalcoholic Steatohepatitis: Pathophysiology and Clinical Implications