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Hepatic triglyceride synthesis and nonalcoholic fatty liver disease.
Curr Opin Lipidol. 2008 Jun; 19(3):295-300.CO

Abstract

PURPOSE OF REVIEW

Nonalcoholic fatty liver disease is a spectrum of diseases ranging from simple steatosis to cirrhosis. The hallmark of nonalcoholic fatty liver disease is hepatocyte accumulation of triglycerides. We will review the role of triglyceride synthesis in nonalcoholic fatty liver disease progression and summarize recent findings about triglyceride synthesis inhibition and prevention of progressive disease.

RECENT FINDINGS

Attempts to inhibit triglyceride synthesis in animal models have resulted in improvement in hepatic steatosis. Studies in animal models of nonalcoholic fatty liver disease demonstrate that inhibition of acyl-coenzyme A:diacylglycerol acyltransferase, the enzyme that catalyzes the final step in triglyceride synthesis, results in improvement in hepatic steatosis and insulin sensitivity. We recently confirmed that hepatic specific inhibition of acyl-coenzyme A:diacylglycerol acyltransferase with antisense oligonucleotides improves hepatic steatosis in obese, diabetic mice but, unexpectedly, exacerbated injury and fibrosis in that model of progressive nonalcoholic fatty liver disease. When hepatocyte triglyceride synthesis was inhibited, free fatty acids accumulated in the liver, leading to induction of fatty acid oxidizing systems that increased hepatic oxidative stress and liver damage. These findings suggest that the ability to synthesize triglycerides may, in fact, be protective in obesity.

SUMMARY

Nonalcoholic fatty liver disease is strongly associated with obesity and peripheral insulin resistance. Peripheral insulin resistance increases lipolysis in adipose depots, promoting increased free fatty acid delivery to the liver. In states of energy excess, such as obesity, the latter normally triggers hepatic triglyceride synthesis. When hepatic triglyceride synthesis is unable to accommodate increased hepatocyte free fatty acid accumulation, however, lipotoxicity results. Thus, rather than being hepatotoxic, liver triglyceride accumulation is actually hepato-protective in obese, insulin-resistant individuals.

Authors+Show Affiliations

Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710, USA.No affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Review

Language

eng

PubMed ID

18460922

Citation

Choi, Steve S., and Anna Mae Diehl. "Hepatic Triglyceride Synthesis and Nonalcoholic Fatty Liver Disease." Current Opinion in Lipidology, vol. 19, no. 3, 2008, pp. 295-300.
Choi SS, Diehl AM. Hepatic triglyceride synthesis and nonalcoholic fatty liver disease. Curr Opin Lipidol. 2008;19(3):295-300.
Choi, S. S., & Diehl, A. M. (2008). Hepatic triglyceride synthesis and nonalcoholic fatty liver disease. Current Opinion in Lipidology, 19(3), 295-300. https://doi.org/10.1097/MOL.0b013e3282ff5e55
Choi SS, Diehl AM. Hepatic Triglyceride Synthesis and Nonalcoholic Fatty Liver Disease. Curr Opin Lipidol. 2008;19(3):295-300. PubMed PMID: 18460922.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Hepatic triglyceride synthesis and nonalcoholic fatty liver disease. AU - Choi,Steve S, AU - Diehl,Anna Mae, PY - 2008/5/8/pubmed PY - 2008/8/6/medline PY - 2008/5/8/entrez SP - 295 EP - 300 JF - Current opinion in lipidology JO - Curr Opin Lipidol VL - 19 IS - 3 N2 - PURPOSE OF REVIEW: Nonalcoholic fatty liver disease is a spectrum of diseases ranging from simple steatosis to cirrhosis. The hallmark of nonalcoholic fatty liver disease is hepatocyte accumulation of triglycerides. We will review the role of triglyceride synthesis in nonalcoholic fatty liver disease progression and summarize recent findings about triglyceride synthesis inhibition and prevention of progressive disease. RECENT FINDINGS: Attempts to inhibit triglyceride synthesis in animal models have resulted in improvement in hepatic steatosis. Studies in animal models of nonalcoholic fatty liver disease demonstrate that inhibition of acyl-coenzyme A:diacylglycerol acyltransferase, the enzyme that catalyzes the final step in triglyceride synthesis, results in improvement in hepatic steatosis and insulin sensitivity. We recently confirmed that hepatic specific inhibition of acyl-coenzyme A:diacylglycerol acyltransferase with antisense oligonucleotides improves hepatic steatosis in obese, diabetic mice but, unexpectedly, exacerbated injury and fibrosis in that model of progressive nonalcoholic fatty liver disease. When hepatocyte triglyceride synthesis was inhibited, free fatty acids accumulated in the liver, leading to induction of fatty acid oxidizing systems that increased hepatic oxidative stress and liver damage. These findings suggest that the ability to synthesize triglycerides may, in fact, be protective in obesity. SUMMARY: Nonalcoholic fatty liver disease is strongly associated with obesity and peripheral insulin resistance. Peripheral insulin resistance increases lipolysis in adipose depots, promoting increased free fatty acid delivery to the liver. In states of energy excess, such as obesity, the latter normally triggers hepatic triglyceride synthesis. When hepatic triglyceride synthesis is unable to accommodate increased hepatocyte free fatty acid accumulation, however, lipotoxicity results. Thus, rather than being hepatotoxic, liver triglyceride accumulation is actually hepato-protective in obese, insulin-resistant individuals. SN - 0957-9672 UR - https://www.unboundmedicine.com/medline/citation/18460922/Hepatic_triglyceride_synthesis_and_nonalcoholic_fatty_liver_disease_ L2 - https://doi.org/10.1097/MOL.0b013e3282ff5e55 DB - PRIME DP - Unbound Medicine ER -