Obeticholic acid raises LDL-cholesterol and reduces HDL-cholesterol in the Diet-Induced NASH (DIN) hamster model

Q: Why are rat and mouse models limited for NASH drug development with OCA?

Their lack of an OCA dyslipidemic effect limits translation because OCA’s effects seen in humans cannot be observed in these rodents.

Q: What makes Golden Syrian hamsters useful for studying OCA in NASH?

They express cholesteryl ester transfer protein (CETP), allowing lipoprotein metabolism to better mimic human dyslipidemia.

Q: How does OCA affect lipid parameters in the Diet-Induced NASH hamster model?

OCA increased CETP activity and LDL-C (by 20% and 27%) and reduced HDL-C (by 20%), compared with diet-fed controls.

Oct 3, 2026

Uploaded by jay

The use of rat and mouse models limits translation for nonalcoholic steatohepatitis (NASH) drug development because obeticholic acid (OCA) dyslipidemic effects seen in humans are not observable in these rodents. Golden Syrian hamsters better mimic human dyslipidemia by expressing cholesteryl ester transfer protein (CETP). A diet-induced NASH hamster model was developed and OCA assessed after 20 weeks of diet and 5 weeks of treatment.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages8

Reading Time20 min

AccessFree to download

Introduction

Rationale for NASH models and OCA translational relevance

Role of CETP and hamster suitability

European Journal of Pharmacology 818 (2018) 449–456 Contents lists available at ScienceDirect European Journal of Pharmacology journal [homepage:](homepage: www.elsevier.com/locate/ejphar)[ www.elsevier.com/locate/ejphar](homepage: www.elsevier.com/locate/ejphar) Cardiovascular pharmacology Obeticholic acid raises LDL-cholesterol and reduces HDL-cholesterol in the Diet-Induced NASH (DIN) hamster model François Brianda,⁎, Emmanuel Brousseaua, Marjolaine Quinsata, Rémy Burcelinb, Thierry Sulpicea a Physiogenex SAS, Prologue Biotech, 516 Rue Pierre et Marie Curie, 31670 Labège-Innopole, France bI2MC, INSERM 1048, Hôpital Rangueil, 31400 Toulouse, France A R T I C L E I N F O Keywords: Nonalcoholic steatohepatitis Obeticholic acid Lipoprotein Cholesterol Hamster A B S T R A C T The use of rat and mouse models limits the translation to humans for developing novel drugs targeting nonalcoholic steatohepatitis (NASH). Obeticholic acid (OCA) illustrates this limitation since its dyslipidemic eﬀect in humans cannot be observed in these rodents. Conversely, Golden Syrian hamsters have a lipoprotein metabolism mimicking human dyslipidemia since it does express the cholesteryl ester transfer protein (CETP). We therefore developed a Diet-Induced NASH (DIN) hamster model and evaluated the impact of OCA. Compared with chow fed controls, hamsters fed for 20 weeks with a free-choice (FC) diet, developed obesity, insulin resistance, dyslipidemia and NASH (microvesicular steatosis, inﬂammation, hepatocyte ballooning and perisinusoidal to bridging ﬁbrosis). After 20 weeks of diet, FC fed hamsters were treated without or with obeticholic acid (15 mg/kg/day) for 5 weeks. Although a non-signiﬁcant trend towards higher dietary caloric intake was observed, OCA signiﬁcantly lowered body weight after 5 weeks of treatment. OCA signiﬁcantly increased CETP activity and LDL-C levels by 20% and 27%, and reduced HDL-C levels by 20%. OCA blunted hepatic gene expression of Cyp7a1 and Cyp8b1 and reduced fecal bile acids mass excretion by 64%(P < 0.05). Hamsters treated with OCA showed a trend towards higher scavenger receptor Class B type I (SR-BI) and lower LDLreceptor hepatic protein expression. OCA reduced NAS score for inﬂammation (P < 0.01) and total NAS score, although not signiﬁcantly. Compared to mouse and rat models, the DIN hamster replicates beneﬁts and side eﬀects ofOCA as observed in humans, and should be useful for evaluating novel drugs targeting NASH. 1. Introduction Due to its tight positive correlation with obesity and type 2 diabetes, the prevalence of nonalcoholic fatty liver diseases (NAFLD) is increasing substantially worldwide (Hardy et al., 2015). NAFLD represent a spectrum of disorders, which range from nonalcoholic fatty liver or simple liver steatosis, to nonalcoholic steatohepatitis (NASH), in which inﬂammatory inﬁltrates, hepatocyte ballooning and ﬁbrosis can be observed, increasing the risk to reach the most severe stages, i.e. cirrhosis and hepatocellular carcinoma (Wree et al., 2013). Concomitant with the growing urbanization level, physical inactivity and consumption of energy dense foods contributes to raise the prevalence of NASH (Farrell, 2003). Increased dietary fructose intake through processed food and beverages consumption is also suspected as a major contributor to NASH, due to the stimulating eﬀect of fructose on hepatic de novo lipogenesis (Kawasaki et al., 2009; Vos and Lavine, 2013; Softicet al., 2016). Although lifestyle and diet changes remain the primary intervention, novel therapies targeting NASH are needed, but no eﬀective drug for NASH treatment is currently available (Sawangjit et al., 2016). To this aim, preclinical mouse and rat models are extensively used to develop these new drugs. A plethora of NASH models are currently available (see Imajo et al. (2013) and Ibrahim et al. (2016) for review), with various approach based on diet induction ([e.g. me](e.g. me)thionine cho

FAQs

Why are rat and mouse models limited for NASH drug development with OCA?

Their lack of an OCA dyslipidemic effect limits translation because OCA’s effects seen in humans cannot be observed in these rodents.

What makes Golden Syrian hamsters useful for studying OCA in NASH?

They express cholesteryl ester transfer protein (CETP), allowing lipoprotein metabolism to better mimic human dyslipidemia.

How does OCA affect lipid parameters in the Diet-Induced NASH hamster model?

OCA increased CETP activity and LDL-C (by 20% and 27%) and reduced HDL-C (by 20%), compared with diet-fed controls.

Oct 3, 2026

Uploaded by jay