Causal relationship of hepatic fat with liver damage and insulin resistance in nonalcoholic fatty liver

P. Dongiovanni, S. Stender, A. Pietrelli, R. M. Mancina, A. Cespiati, S. Petta, S. Pelusi, P. Pingitore, S. Badiali, M. Maggioni, V. Mannisto, S. Grimaudo, R. M. Pipitone, J. Pihlajamaki, A. Craxi, M. Taube, L. M.S. Carlsson, S. Fargion, S. Romeo, J. KozlitinaL. Valenti

Research output: Contribution to journalArticle

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Abstract

Background and Aims: Nonalcoholic fatty liver disease is epidemiologically associated with hepatic and metabolic disorders. The aim of this study was to examine whether hepatic fat accumulation has a causal role in determining liver damage and insulin resistance. Methods: We performed a Mendelian randomization analysis using risk alleles in PNPLA3, TM6SF2, GCKR and MBOAT7, and a polygenic risk score for hepatic fat, as instruments. We evaluated complementary cohorts of at-risk individuals and individuals from the general population: 1515 from the liver biopsy cohort (LBC), 3329 from the Swedish Obese Subjects Study (SOS) and 4570 from the population-based Dallas Heart Study (DHS). Results: Hepatic fat was epidemiologically associated with liver damage, insulin resistance, dyslipidemia and hypertension. The impact of genetic variants on liver damage was proportional to their effect on hepatic fat accumulation. Genetically determined hepatic fat was associated with aminotransferases, and with inflammation, ballooning and fibrosis in the LBC. Furthermore, in the LBC, the causal association between hepatic fat and fibrosis was independent of disease activity, suggesting that a causal effect of long-term liver fat accumulation on liver disease is independent of inflammation. Genetically determined hepatic steatosis was associated with insulin resistance in the LBC and SOS. However, this association was dependent on liver damage severity. Genetically determined hepatic steatosis was associated with liver fibrosis/cirrhosis and with a small increase in risk of type 2 diabetes in publicly available databases. Conclusion: These data suggest that long-term hepatic fat accumulation plays a causal role in the development of chronic liver disease.

Original languageEnglish
Pages (from-to)356-370
Number of pages15
JournalJournal of Internal Medicine
Volume283
Issue number4
DOIs
Publication statusPublished - Apr 1 2018

Fingerprint

Insulin Resistance
Fats
Liver
Liver Cirrhosis
Biopsy
Non-alcoholic Fatty Liver Disease
Mendelian Randomization Analysis
Liver Diseases
Inflammation
Dyslipidemias
Transaminases
Type 2 Diabetes Mellitus
Population
Fibrosis
Chronic Disease

Keywords

  • fibrosis
  • genetics
  • insulin resistance
  • mendelian randomization
  • nonalcoholic fatty liver disease
  • type 2 diabetes

ASJC Scopus subject areas

  • Internal Medicine

Cite this

Causal relationship of hepatic fat with liver damage and insulin resistance in nonalcoholic fatty liver. / Dongiovanni, P.; Stender, S.; Pietrelli, A.; Mancina, R. M.; Cespiati, A.; Petta, S.; Pelusi, S.; Pingitore, P.; Badiali, S.; Maggioni, M.; Mannisto, V.; Grimaudo, S.; Pipitone, R. M.; Pihlajamaki, J.; Craxi, A.; Taube, M.; Carlsson, L. M.S.; Fargion, S.; Romeo, S.; Kozlitina, J.; Valenti, L.

In: Journal of Internal Medicine, Vol. 283, No. 4, 01.04.2018, p. 356-370.

Research output: Contribution to journalArticle

Dongiovanni, P, Stender, S, Pietrelli, A, Mancina, RM, Cespiati, A, Petta, S, Pelusi, S, Pingitore, P, Badiali, S, Maggioni, M, Mannisto, V, Grimaudo, S, Pipitone, RM, Pihlajamaki, J, Craxi, A, Taube, M, Carlsson, LMS, Fargion, S, Romeo, S, Kozlitina, J & Valenti, L 2018, 'Causal relationship of hepatic fat with liver damage and insulin resistance in nonalcoholic fatty liver', Journal of Internal Medicine, vol. 283, no. 4, pp. 356-370. https://doi.org/10.1111/joim.12719
Dongiovanni, P. ; Stender, S. ; Pietrelli, A. ; Mancina, R. M. ; Cespiati, A. ; Petta, S. ; Pelusi, S. ; Pingitore, P. ; Badiali, S. ; Maggioni, M. ; Mannisto, V. ; Grimaudo, S. ; Pipitone, R. M. ; Pihlajamaki, J. ; Craxi, A. ; Taube, M. ; Carlsson, L. M.S. ; Fargion, S. ; Romeo, S. ; Kozlitina, J. ; Valenti, L. / Causal relationship of hepatic fat with liver damage and insulin resistance in nonalcoholic fatty liver. In: Journal of Internal Medicine. 2018 ; Vol. 283, No. 4. pp. 356-370.
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abstract = "Background and Aims: Nonalcoholic fatty liver disease is epidemiologically associated with hepatic and metabolic disorders. The aim of this study was to examine whether hepatic fat accumulation has a causal role in determining liver damage and insulin resistance. Methods: We performed a Mendelian randomization analysis using risk alleles in PNPLA3, TM6SF2, GCKR and MBOAT7, and a polygenic risk score for hepatic fat, as instruments. We evaluated complementary cohorts of at-risk individuals and individuals from the general population: 1515 from the liver biopsy cohort (LBC), 3329 from the Swedish Obese Subjects Study (SOS) and 4570 from the population-based Dallas Heart Study (DHS). Results: Hepatic fat was epidemiologically associated with liver damage, insulin resistance, dyslipidemia and hypertension. The impact of genetic variants on liver damage was proportional to their effect on hepatic fat accumulation. Genetically determined hepatic fat was associated with aminotransferases, and with inflammation, ballooning and fibrosis in the LBC. Furthermore, in the LBC, the causal association between hepatic fat and fibrosis was independent of disease activity, suggesting that a causal effect of long-term liver fat accumulation on liver disease is independent of inflammation. Genetically determined hepatic steatosis was associated with insulin resistance in the LBC and SOS. However, this association was dependent on liver damage severity. Genetically determined hepatic steatosis was associated with liver fibrosis/cirrhosis and with a small increase in risk of type 2 diabetes in publicly available databases. Conclusion: These data suggest that long-term hepatic fat accumulation plays a causal role in the development of chronic liver disease.",
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AU - Stender, S.

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AU - Mancina, R. M.

AU - Cespiati, A.

AU - Petta, S.

AU - Pelusi, S.

AU - Pingitore, P.

AU - Badiali, S.

AU - Maggioni, M.

AU - Mannisto, V.

AU - Grimaudo, S.

AU - Pipitone, R. M.

AU - Pihlajamaki, J.

AU - Craxi, A.

AU - Taube, M.

AU - Carlsson, L. M.S.

AU - Fargion, S.

AU - Romeo, S.

AU - Kozlitina, J.

AU - Valenti, L.

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N2 - Background and Aims: Nonalcoholic fatty liver disease is epidemiologically associated with hepatic and metabolic disorders. The aim of this study was to examine whether hepatic fat accumulation has a causal role in determining liver damage and insulin resistance. Methods: We performed a Mendelian randomization analysis using risk alleles in PNPLA3, TM6SF2, GCKR and MBOAT7, and a polygenic risk score for hepatic fat, as instruments. We evaluated complementary cohorts of at-risk individuals and individuals from the general population: 1515 from the liver biopsy cohort (LBC), 3329 from the Swedish Obese Subjects Study (SOS) and 4570 from the population-based Dallas Heart Study (DHS). Results: Hepatic fat was epidemiologically associated with liver damage, insulin resistance, dyslipidemia and hypertension. The impact of genetic variants on liver damage was proportional to their effect on hepatic fat accumulation. Genetically determined hepatic fat was associated with aminotransferases, and with inflammation, ballooning and fibrosis in the LBC. Furthermore, in the LBC, the causal association between hepatic fat and fibrosis was independent of disease activity, suggesting that a causal effect of long-term liver fat accumulation on liver disease is independent of inflammation. Genetically determined hepatic steatosis was associated with insulin resistance in the LBC and SOS. However, this association was dependent on liver damage severity. Genetically determined hepatic steatosis was associated with liver fibrosis/cirrhosis and with a small increase in risk of type 2 diabetes in publicly available databases. Conclusion: These data suggest that long-term hepatic fat accumulation plays a causal role in the development of chronic liver disease.

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KW - mendelian randomization

KW - nonalcoholic fatty liver disease

KW - type 2 diabetes

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