Weight loss amelioration of non-alcoholic steatohepatitis linked to shifts in hepatic ceramide expression and serum ceramide levels
Open accessAbstract
Aim: Non‐alcoholic steatohepatitis (NASH) is associated with increased hepatic insulin resistance. Ceramides and other toxic sphingolipids promote inflammation, lipotoxicity and insulin resistance; however, the role of ceramides in the pathogenesis of NASH has not been determined. This study characterizes expression of ceramide‐related genes in human livers with NASH and examines the effects of weight loss on NASH and pro‐ceramide gene expression in liver. Methods: Liver biopsies were obtained to assess the histopathological status of non‐alcoholic fatty liver disease/NASH prior to and following completion of a 1‐year course of implementing either lifestyle changes or a standard enrichment protocol designed to encourage weight loss. Liver biopsy samples were used to measure pro‐ceramide gene expression by quantitative reverse transcriptase polymerase chain reaction analysis (qRT–PCR), and serum was used to measure ceramide immunoreactivity. Results: At baseline, serine palmitoyltransferase (SPTLC)2 (P = 0.02) and ceramide synthase (CER)1 (P = 0.001) mRNA transcripts were less abundantly expressed in livers with NASH relative to normal controls. After weight loss (average 9.3%), SPTLC1 (P = 0.005) and uridine diphosphate glucose ceramide glucosyltransferase (UGCG) (P = 0.001) expression significantly declined while CER1 increased (P = 0.001) among subjects randomized to the lifestyle change subgroup. Reductions in calorie and fat consumption were significantly correlated with changes in ceramide‐related gene expression. Finally, both net and relative reductions in serum ceramide levels were significantly greater in the lifestyles compared with the standard enrichment (control) protocol group (both P < 0.005). Conclusion: NASH is associated with increased insulin resistance and altered ceramide gene expression in liver. Weight loss‐mediated reversal of NASH is associated with reduced pro‐ceramide gene expression in liver.
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Promrat et al. showed that MASH was associated with lower hepatic expression of ceramide synthase 1 (CERS1), while 1 year of lifestyle intervention (with weight loss) reduced SPTCL1 expression and plasma ceramides.
“Promrat et al.117 showed that MASH was associated with lower hepatic expression of ceramide synthase 1 (CERS1), while 1 year of lifestyle intervention (with weight loss) reduced SPTCL1 expression and plasma ceramides.”
From Lipid metabolism in MASLD and MASH: From mechanism to the clinic (2024) · cites this paper as [117]
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The Liver as an Endocrine Organ—Linking NAFLD and Insulin Resistance
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Lipid metabolism in MASLD and MASH: From mechanism to the clinic
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- Authors
- Promrat, K., Longato, L., Wands, J. R., & de la Monte, S. M.
- Affiliations
- Brown University (US)
- Rhode Island Hospital (US)
- Corresponding author
- Promrat, Kittichai
- Venue
- Hepatology Research
- Publisher
- Wiley
- Published
- 2011-07-24
- Volume
- 41
- Issue
- 8
- Pages
- 754-762
- ISSN
- 1386-6346 (ISSN-L)
- 1872-034X
- PMC
- PMC4550290
- OpenAlex
- W2130239265
- Cited by
- 66
- References
- 46
- Citations by year
- 2025: 5 · 2024: 8 · 2023: 7 · 2022: 9 · 2021: 1 · 2020: 5 · 2019: 4 · 2018: 3 · 2017: 4 · 2016: 4 · 2015: 2 · 2014: 3 · 2013: 3 · 2012: 7
- FWCI
- 3.12
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Hepatology Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- National Institutes of Health (5r01aa011431-26)
- National Institute on Alcohol Abuse and Alcoholism (R01-AA011431, K24AA016126, R56AA011431, R01AA012908, R37AA011431)
- National Cancer Institute (R01CA123544)
- National Institute of Diabetes and Digestive and Kidney Diseases (R03DK067263)
- Topics
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sphingolipid Metabolism and Signaling
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diet, Metabolism, and Disease
- Keywords
- nonalcoholic steatohepatitis, weight loss, ceramide, sphingolipids, hepatic insulin resistance, ceramide synthase, serine palmitoyltransferase, UGCG, ceramide glucosyltransferase, non-alcoholic fatty liver disease, lifestyle intervention, gene expression
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